Method and apparatus for controlled environment electrotransport

ABSTRACT

Methods for conducting operation of an electrode arrangement are described. The methods generally concern use of an electrode reservoir containing both a first electrode and a secondary electrode. A system for practicing the methods is also provided.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation application of U.S. Ser. No.08/451,119, filed on May 26, 1995, now U.S. Pat. No. 5,622,530, issuedon Apr. 22, 1997. U.S. Ser. No. 08/451,119 was a divisional applicationof U.S. Ser. No. 08/173,149, filed on Dec. 22, 1993, now U.S. Pat. No.5,443,442, issued on Aug. 22, 1995. U.S. Ser. No. 08/173,149 was acontinuation application of U.S. Ser. No. 07/831,804, filed Feb. 5,1992, now abandoned. U.S. Ser. No. 07/831,804 was a divisional of U.S.Ser. No. 07/502,232, filed on Mar. 30, 1990, now U.S. Pat. No.5,125,894, issued on Jun. 30, 1992. In this patent family there is alsoapplication U.S. Ser. No. 08/452,403 filed May 26, 1995 as a divisionalof Ser. No. 08/173,149, which issued as U.S. Pat. No. 5,591,124 on Jan.7, 1997. The specification and drawings of application Ser. No.08/451,119 are incorporated herein by reference. A claim of priorityback to U.S. Ser. No. 07/502,232 filed Mar. 30, 1990 is made.

FIELD OF THE INVENTION

The present invention generally concerns methods and apparatus forelectrotransport. More specifically, methods of the present inventionconcern conduction of electrotransport with selected control of activeelectrode reservoir environment, to advantage. The present inventionalso specifically concerns apparatus for providing controlled activeelectrode environment electrotransport. Two methods of electrotransportto which the invention has particular preferred application areiontophoresis and electro-osmosis. Some of the principles describedherein may be applied to passive delivery processes (not involvingelectrotransport) to advantage.

BACKGROUND OF THE INVENTION

The present invention concerns preferred methods and apparatus fortransdermal delivery or transport of therapeutic agents, typicallythrough electrotransport. Herein the term "electrotransport" is used torefer to methods and apparatus for transdermal delivery of therapeuticagents, whether charged or uncharged, by means of an appliedelectromotive force to electrolyte-containing reservoir. The particulartherapeutic agent being delivered may be charged or uncharged, dependingupon the particular method chosen. When the therapeutic species beingdelivered is charged, the process is referred to as iontophoresis. Whenthe therapeutic species delivered is uncharged, it may be considereddelivered by means of electro-osmosis techniques or other electrokineticphenomenon such as electrohydrokinesis, electro-convection orelectrically-induced osmosis. In general, these latter electrokineticdelivery processes of uncharged species into a tissue result from themigration of solvent, in which the uncharged species is dissolved, as aresult of the application of electromotive force to the electrolytereservoir. Of course during the process, some transport of chargedspecies will take place as well.

In general, iontophoresis is an introduction, by means of electriccurrent, of ions of soluble salts into the tissues of the body. Morespecifically, iontophoresis is a process and technique which involvesthe transfer of ionic (charged) species into a tissue (for examplethrough the skin of a patient) by the passage of a electric currentthrough an electrolyte solution containing ionic molecules to bedelivered (or precursors for those ions), upon application of anappropriate electrode polarity. That is, ions are transferred into thetissue, from an electrolyte reservoir, by application of electromotiveforce to the electrolyte reservoir.

Much of the discussion herein will focus on techniques foriontophoresis, and apparatus therefor. However, the methods andapparatus will be understood to be applicable to electrotransportgenerally, including electrokinetic phenomena involving transport of anuncharged therapeutic species. A reason for this, is that such phenomenagenerally involve the transport of some charged species, which isaccompanied by the desired movement of an uncharged therapeutic species.

Assume, for example, that the patient to receive the therapeutic iontreatment is a human and the medication is to be transferred through theskin. Through iontophoresis, either positively charged drugs(medication) or negatively charged drugs (medication) can be readilytransported through the skin and into the patient. This is done bysetting up an appropriate potential between two electrode systems (anodeand cathode) in electrical contact with the skin. If a positivelycharged drug is to be delivered through the skin, an appropriateelectromotive force can be generated by orienting the positively chargeddrug species at a reservoir associated with the anode. Similarly, if theion to be transferred across the skin is negatively charged, appropriateelectromotive force can be generated by positioning the drug in areservoir at the cathode. Of course, a single system can be utilized totransfer both positively charged and negatively charged drugs into apatient at a given time; and, more than one cathodic drug and/or morethan one anodic drug may be delivered from a single system during aselected operation. For general discussions of iontophoresis see:Phipps, J. B. et al; "Transport of Ionic Species Through Skin"; SolidState Ionics; Vol. 28-30, p. 1778-1783 (1988); Phipps, J. B., et al;"Iontophoretic Delivery of Model Inorganic and Drug Ions"; J. Pharm.Sciences; Vol. 78, No. 5, p. 365-369 (May 1989); and, Chien, Y.W. et al;"Iontophoretic Delivery of Drugs: Fundamentals, Developments andBiomedical Applications"; J. Controlled Release, Vol. 7, p. 1-24 (1988).The disclosures of these three references are incorporated herein byreference.

Electrotransport processes, including iontophoresis, have found a widevariety of therapeutic applications. Such applications have sometimesinvolved the delivery of ionic drugs, i.e., charged organic medicationsor therapeutic metal ions. Applications have involved both treatments ofconditions and also diagnostics. For example, iontophoresis techniqueshave been utilized to deliver pilocarpine, a substance utilized in thediagnosis of cystic fibrosis. It has also been utilized to deliverhyaluronidase, for treatment of scleroderma and lymphedema. It hasfurther been utilized for allergy testing, delivery of metallic ions fortreatment of fungal infections, venereal diseases, ulcers, bursitis, andmyopathies; delivery of vasodilators; and, for delivery of anestheticsand steroids. See for example Chien, Y. W., et al., supra.

A wide variety of iontophoresis devices are presently known. See forexample: Phipps et al., U.S. Pat. No. 4,744,788; Phipps et al., U.S.Pat. No. 4,747,819; Tapper et al., European Patent ApplicationPublication No. 0318776; Jacobsen et al., European Patent ApplicationPublication No. 0299631; Petelenz et al., U.S. Pat. No. 4,752,285;Sanderson et al., U.S. Pat. No. 4,722,726; and Parsi, E.J., U.S. Pat.No. 4,731,049. The disclosures of these seven references areincorporated herein by references.

In typical, conventional, electrotransport devices, for exampleiontophoresis devices, two electrodes are generally used. Bothelectrodes are disposed so as to be an intimate electrical contact withsome portion (typically skin) of the subject (human or animal) typicallyby means of two remote electrolyte-containing reservoirs, between whichcurrent passes as it moves between the skin and the electrodes. Oneelectrode, generally referred to herein as the "active" electrode, isthe electrode from which the substance (medicament, drug precursor ordrug) is delivered or driven into the body by application of theelectromotive force. The other electrode, typically referred to as an"indifferent" or "ground" electrode, serves to close the electricalcircuit through the body. In some instances both electrodes may be"active", i.e. drugs may be delivered from both. In such cases eachelectrode will serve as the "companion", "indifferent", "remote" or"ground" electrode, to the other. That is, classification of anelectrode as "active" or "indifferent" is done by reference to aparticular material being delivered. Herein the term electrode, orvariants thereof, when used in this context refers to an electricallyconductive member, through which a current passes during operation.

If the electrotransport method is iontophoresis, generally the activeelectrode includes the therapeutic species as a charged ion, or aprecursor for the charged ion, and the transport occurs throughapplication of the electromotive force to the charged therapeuticspecies. If other electrotransport phenomenon are involved, thetherapeutic species will be delivered in an uncharged form, transferbeing motivated, however, by electromotive force. For example, theapplied current may induce movement of a non-therapeutic species, whichcarries with it water into the subject. The water may have dissolvedtherein the therapeutic species. Thus, electrotransport of thenon-therapeutic charged species induces movement of the therapeutic butnon-charged species.

In conjunction with the patient's skin in electrical communication withthe electrodes, the circuit is completed by connection of the twoelectrodes to a source of electrical energy as a direct current; forexample, a battery or a source of appropriately modified alternatingcurrent. As an example, if the ionic substance to be driven to the bodyis positively charged, then the positive electrode (the anode) will bethe active electrode and the negative electrode (the cathode) will serveto complete the circuit. If the ionic substance to be delivered isnegatively charged, then the negative electrode (cathode) will be theactive electrode and the positive electrode (anode) will be theindifferent electrode.

Again, electrotransport devices generally require a reservoir as asource of the species (or a precursor of such species) which is to bemoved or introduced into the body. If the device is an iontophoresisdevice, in general the reservoir is a pool of electrolyte solution, forexample an aqueous electrolyte solution or a hydrophilic,electrolyte-containing, gel or gel matrix or absorbent material. Suchdrug reservoirs, when electrically connected to the anode or the cathodeof an iontophoresis device, provide a source of one or more ionicspecies for electrotransport.

Herein, for electrotransport processes, the reservoir associated withthe active electrode will be referred to as the "active electrodereservoir." It is this reservoir which includes the "target species" or"therapeutic species," for transport; if as a charged species morespecifically for electrotransport. The reservoir associated with theother electrode will be referred to herein as the "inactive" or"indifferent" electrode reservoir.

Systems of particular interest to the present application are "closed"reservoir systems. These are systems in which the active electrodereservoir is not replenished during operation, by a remote source ofelectrolyte solution. Thus, changes in reservoir content duringelectrotransport will generally be those due to the electrode operation(in addition to diffusion).

During many conventional electrotransport processes, ionic species, inaddition to the charged drug species or therapeutic species to betransported, are generated or provided at the active electrode. Forexample, if the active electrode is the anode, and it is formed from ametal oxidizable under the operating potentials of the system, it willserve as a source of metal cations corresponding to the material fromwhich the electrode is made. Also, again as an example, hydronium ioncontent (i.e. pH) may change during operation of certain electrodes(e.g., platinum, glass carbon or stainless steel electrodes).

During iontophoresis, since the therapeutic agent(s) is charged, it mustcompete with other similarly charged ions in the reservoir, forelectrotransport through the skin and into the patient under theelectromotive force of the applied potential. For example, if the activeelectrode is the anode, and the drug is to be delivered in a positivelycharged form, the positively charged drug must compete for transportwith all other positively charged species in the reservoir or formedduring the operation of the electrode and allowed to remain in solutionin the reservoir. It follows, then, that for a constant current,efficiency of transport of the desired drug species across the skinmembrane is reduced, if the operation of the active electrode involvesgeneration of (or motivation of) competing species in the activeelectrode reservoir. This observation will hold whether the activeelectrode is the anode or the cathode.

Herein species in the active electrode reservoir similarly charged tothe selected species for electrotransport (or transport) byiontophoresis (i.e. similarly charged to the target or therapeutic ionsT_(i)) will be referred to as "extraneous" ions (X_(i)). For example, ifthe drug species to be selectively transferred is a positively chargedspecies, all other cations in the active electrode reservoir will bereferred to as "extraneous" ions or "extraneous cations". Alternatively,if the drug or treatment species to be transferred across the skin isnegatively charged, all other anionic species in the active electrodereservoir will be referred to as "extraneous ions" or "extraneousanions". In general, the presence of extraneous ions reduces theefficiency of transport of a selected (i.e. target or therapeutic) ion,for a given iontophoresis system.

Alternatively, extraneous ions may be defined as those ions which willbe transported from an active electrode reservoir, under appliedpotential, other than therapeutic species (if the therapeutic species ischarged). That is, if the therapeutic species is uncharged, extraneousions will be those ions which are delivered from the reservoir under theapplied potential, during operation of the system.

Herein the term "target species", or "therapeutic species" and variantsthereof refer in general to the agent to be selectively transported intosubject for example by application of potential, whether that species ischarged or not. Herein the terms "target ion", "therapeutic ion"andvariants thereof refer to the particular ion species to be delivered bythe iontophoresis process for therapy. In many instances the target ionwill be a drug ion, or a selected metal ion. These species need not bethe precise therapeutic agent(s) which operate in the body of thesubject. They could, for example, be precursors to such agents. Theterms are also intended to include within their scope ions delivered forpurposes other than to treat some condition, for example to facilitatediagnoses. Thus, herein the term "therapy" and variants thereof is meantto include treatments of conditions, diagnostic procedures and otherprocesses of medicine wherein an agent is delivered to a subject.

Methods have been developed to generate relatively extraneous ion free,or reduced extraneous ion concentration, systems. See for example themethods and apparatus described in U.S. Pat. Nos. 4,747,819 and4,744,787 to Phipps et al., incorporated herein by reference andassigned to Medtronic, Inc., Minneapolis, Minn., the assignee of theinstant invention. A basic principle of these methods is that the activeelectrode and/or components of the active electrode reservoir areselected such that electrochemical reactions conducted at the activeelectrode during operation provide species which do not interfere withor compete with the selected ionic species for transport (i.e. thetarget or therapeutic ion species). For example, if the drug to bedelivered is positively charged, and it exists in the reservoir as ahydrochloride salt, the active electrode will be the anode. If a silver(or silver/silver chloride) electrode were used as the anode, thenduring operation of the electrode, a positive ion species formed at theanode would be silver cations. The reservoir includes chloride ions insolution from the hydrochloride salt of the drug, so silver chloride(which is insoluble) would be continuously formed during electrodeoperation. The silver chloride would precipitate from solution, at thesurface of the active electrode. The result, then, would be continuousoperation of the electrode to provide electromotive force to thecationic drug ion, without addition of positively charged species,(i.e., silver cations as extraneous cations) to the anodic reservoir ina mobile form. Thus, the concentration of extraneous ions in the activeelectrode reservoir is maintained at a minimum, or at least is notincreased through operation of the system.

It is not, in practice, practical to completely exclude extraneous ionfrom typical electrotransport systems. The reasons for this include thefact that the hydrophilic reservoirs (typically aqueous systemsinvolving gels or gel matrices) often may include therein, in additionto the drug species to be delivered (or a precursor for the drug speciesto be delivered) buffers, antibacterial agents, etc. Further, it mayjust be impractical in many instances to provide for a complete absenceof ions (other than any ions to be selectively transported) and completesuppression of formation of such ions during electrode operation. Thus,even if the methods of Phipps et al. '787 and '819 are practiced toavoid introduction of more extraneous ions into a system, typicaliontophoresis systems will in general include, ab initio, a significantconcentration of extraneous ions. As will be seen in discussions below,this concentration of extraneous ions can have a significant effect onthe performance of the iontophoresis process. In some instances it willnegatively effect the process.

SUMMARY OF THE INVENTION

The present invention generally concerns controlled environmentelectrotransport techniques and methods, and also apparatus forconducting controlled environment electrotransport processes. The term"controlled environment electrotransport" and variants thereof, as usedherein, refers to electrotransport methods wherein the ionic content ofthe active electrode reservoir is selectively controlled, to achievedesired results. Examples are to maintain control of ionic content toselectively control rate of delivery of target species, or to controlenvironmental parameters such as pH or conductivity. In certainpreferred applications the electrotransport technique involved will beiontophoresis, so the process would generally be a controlledenvironment iontophoresis.

In general, methods of conducting controlled environmentelectrotransport according to the present invention comprise conductingelectrotransport with: selected operation of a primary electrodearrangement to provide electromotive force for transport of targetspecies from an active electrode reservoir; and, selected operation of asecondary electrode arrangement, different from (or in a differentmanner than) the primary electrode arrangement, to selectively affectrelative concentrations of ions in the active electrode reservoir. Ingeneral, the secondary electrode arrangement may be operatedcontinuously or periodically. The secondary electrode arrangement may beoperated while the primary electrode arrangement is operated, or, insome applications, it may be operated while no current flows through theprimary electrode arrangement. In those applications in which both theprimary electrode arrangement and the secondary electrode arrangementare operated at the same time (at least part of the time) relativecurrent flow through the primary electrode arrangement and the secondaryelectrode arrangement may be varied, during the process. Either maycarry the higher percentage of current, at any given time. Both may beconducted as anodes, both as cathodes, and in some applications one asthe anode and the other as a cathode.

Herein the term "electrotransport", "transport" and variants thereof, inthis context, refers to transfer of ions from the active electrodereservoir, by means of applied electromotive force. Losses of ioncontent through other means, for example diffusion, or electrochemicalchange, are not generally included within this utilization of the terms.In general, the methods are particularly well adapted for conductingelectrotransport wherein the active electrode reservoir includes targetspecies and extraneous ion species; and it is particularly useful forapplications wherein the target species is charged (i.e., is ionic).Herein the term "target ion species" refers to therapeutic ions or otherions to be transferred from the electrode reservoir, for medicalpurposes. For example, the target ion species may be a drug species tobe delivered to a patient, a precursor for such a drug species, atherapeutic metal ion species, a species utilized in some form ofdiagnostic procedure, or a species used to facilitate theelectro-osmotic delivery of uncharged therapeutic agents. The target ionspecies may be either a cationic species or an anionic species,depending upon the system of concern. The term "extraneous ions"generally refers to ions other than the therapeutic or target species inthe active electrode reservoir which will feel the electromotive forcefor delivery to the subject, during electrode operation. If the targetspecies is ionic (i.e., the process is iontophoresis), extraneous ionsare ions of an analogous charge (in sign) to the target ion(s), butdifferent from the target ion(s).

In some preferred applications the secondary electrode arrangement isoperated to selectively maintain a level of a particular extraneous ionspecies in the active electrode reservoir as a constant. For example, itmay be operated to maintain a constant pH (i.e., hydronium ion content)in the active electrode reservoir. Herein, when it is said that theconcentration of a species is maintained substantially constant, it ismeant that it is preferably maintained at a particular value ± about30.0% of that value, and more preferably ± no greater than about 10.0%of that value.

In some preferred applications of the present invention, the secondaryelectrode arrangement is operated to electrochemically introduce intothe active electrode reservoir a species which is also being lost, dueto diffusion and/or the electromotive force applied to the activeelectrode reservoir for transport of ions therefrom.

In some preferred applications, it may be desirable to replace lostextraneous ions at the very same rate they are lost, for example tomaintain constant pH as indicated above. In other instances, it may bedesirable to replace them at a rate different from their loss, in orderto achieve some desired effect. For example, if the rate of loss ofextraneous ions, due to electromotive force supplied by the primaryelectrode arrangement, is such as would undesirably affect the rate ofdelivery of the target species (if not accounted for), the secondaryelectrode arrangement can be operated in order to replace the lostextraneous ions at a rate so as to maintain a desired rate of deliveryfor the target species. A specific example of this, as will be seen fromdetailed descriptions below, is operation of the secondary electrodearrangement, during iontophoresis, in a manner to maintain a constantmolar fraction of a target ion species within the active electrodearrangement.

Herein when it is said that a molar fraction of a target ion ismaintained at a substantially constant level, it is meant that it ispreferably maintained within about 30.0%, more preferably within about10.0%, of that level throughout the electrotransport process.

As will be seen from the detailed descriptions, in some preferredapplications it may be useful to operate the secondary electrodearrangement to remove extraneous ions. In still other applications, itmay be desirable to operate the secondary electrode to change thepresence (i.e., by removal or addition) of the target species. Hereinwhen it is said that the secondary electrode arrangement is operated toaffect the presence of a species (by removal or addition) it is meant bymeans other than, or in addition to, mere transport to the subject orelsewhere. In addition, it is meant that the effect is different fromthat resulting from the primary electrode arrangement.

In preferred applications, the processes are conducted in a manner suchthat total current flow through a subject of the iontophoresis ismaintained substantially constant. That is, current flow between theactive electrode reservoir and the companion electrode reservoir, bypassage through the subject, is maintained substantially constant.Herein when it is said that the total current flow is maintainedsubstantially constant, it is meant that it is maintained within about30.0% of a particular figure, more preferably when at about 10% of thatfigure, throughout the electrotransport process. Maintenance of aconstant current flow may be conducted by adjustment, as necessary, ofrelative current flow between the primary electrode arrangement and thesecondary electrode arrangement, within the active electrode reservoir.

A preferred apparatus according to the present invention, usable forconduction of processes according to the present invention, is anelectrotransport apparatus comprising: an active electrode reservoir; aprimary electrode arrangement in electrically conductive contact withthe active electrode reservoir; and, a secondary electrode arrangementin electrically conductive contact with the active electrode reservoir,the secondary electrode arrangement being different from (or operablydifferent from), and isolated from direct contact with, the primaryelectrode arrangement. The two electrode arrangements may be constructedfor operation either at the same time or at selected times relative toone another. In some preferred systems, the arrangement includes meansfor selective, simultaneous, operation of both the primary and thesecondary electrode arrangements. To be operable, both the primaryelectrode arrangement and the secondary electrode arrangement should bein electrically conductive contact with the electrolyte-containingmedium, in the active electrode reservoir. The electrolyte medium in theactive electrode reservoir may be an aqueous electrolyte-containingsolution, or an electrolyte-containing gel or gel matrix, etc., as arecommonly used in electrotransport.

Preferred apparatus includes a control means, for controlling currentflow through the primary electrode arrangement and the secondaryelectrode arrangement. Preferably the control means includes means formaintenance of a constant current, if desired, through a subject of theelectrotransport process.

Certain preferred apparatus include sensor means for detecting aselected characteristic of the active electrode reservoir. That selectedcharacteristic may be, for example, total ion content, organic ioncontent, inorganic ion content, or content of some specific ion. It mayalso be, for example, means for detecting some physical characteristicof the electrolyte-containing material in the active electrodereservoir, which can be related to ion presence, for example,conductance. The sensor means for operation as described may include forexample a pH meter, an optical sensor, an ion selective electrode, or aconductance measurement device. Preferably the sensor means ispositioned in a portion of the active electrode reservoir immediatelyadjacent the skin surface of a subject of the electrotransport process,as measurement of ion concentration or electrolyte-containing solutioncharacteristics immediately adjacent to a subject (i.e., adjacent to thesurface through which transport occurs), is most important.

A preferred electrotransport apparatus generally usable in preferrediontophoresis processes according to the present invention includes: anactive electrode reservoir including a concentration of target ions anda concentration of extraneous ions; and, means for maintaining asubstantially constant rate of delivery of selected ions (typicallytarget or therapeutic ions for iontophoresis) from the active electrodereservoir, during operation of the apparatus. This means may beprovision of arrangement including a primary electrode system and asecondary electrode system, as described above, when coupled withappropriate control means. In particular, the control means and primaryand secondary electrode system should be such that a molar concentrationof the target ions for transport can be maintained substantiallyconstant, throughout the iontophoresis process. Preferably means arealso provided, to control the rate of delivery of the target species,while maintaining a constant current flow through the subject of theiontophoresis process.

Another preferred electrotransport apparatus according to the presentinvention includes: an active electrode reservoir including aconcentration of target species and a concentration of extraneous ions;and, means for maintaining a concentration of a selected extraneous ionspecies in the active reservoir substantially constant, throughoutoperation. An example would be maintenance of constant pH, through useof a secondary electrode arrangement. A particular preferred sucharrangement is one wherein the secondary electrode arrangement is aniridium oxide arrangement; i.e. an electrode operable foroxidation/reduction reactions of Ir(III) and Ir(IV). If desired, a pHsensor feedback arrangement can be used to facilitate control.

In some preferred applications, the two electrodes in a deliveryreservoir can be used to facilitate disposal of the reservoir at the endof a delivery process. For example, they can be operated to render anyresidual drug species therein inactive, for convenient disposal. Eitherpre-programming or sensor means can be used to facilitate this process.

In some applications, techniques and apparatus described herein may beused to facilitate passive delivery of species (i.e. delivery throughdiffusion rather than electrotransport) by operation of primary andsecondary electrodes in a reservoir to control the concentration ofdiffusible species in the reservoir. For example, if a drug species hasa charged form and an uncharged form, and the uncharged form of a drugspecies is more mobile (through diffusion) than the charged form, thetechniques described can be used to control pH of the reservoir tocontrol concentration of (and hence rate of delivery of) the unchargedform. Such a process would not necessarily concern electrotransport, butit would be an advantageous application of principles described herein.

The principles of the present invention may be applied to a systeminvolving pulsed operation; for example, wherein pulses of current passthrough the subject.

Further regarding general processes and advantages to the presentinvention will be understood from the following detailed descriptions.The descriptions are intended to be exemplary of the general principlesof the invention, not otherwise limiting of the general applications andprinciples of the present invention. It is noted that in the drawings insome instances relative material or component thicknesses or sizes maybe shown exaggerated, to facilitate understanding.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph indicating change in the rate of delivery of aparticular drug species, with time, for four different systems involvingextraneous ions; the experiment to which FIG. 1 is related beingdescribed in Experiment 1.

FIG. 2 is a schematic representation generally indicating apparatususable according to the invention.

FIG. 3 is a cross-sectional view of a particular preferred apparatususable according to the present invention, shown operationallypositioned against a skin surface of a subject.

FIG. 4 is a top plan view of the arrangement shown in FIG. 3.

FIG. 5 is a graph representing pH changes with electrode operation, asdescribed herein for an iridium oxide electrode.

FIG. 6 is a graph representing linear dependence of ion delivery rate,for the experiment described in Experiment 2.

DETAILED DESCRIPTION OF THE INVENTION A. Some General ObservationsRegarding Iontophoresis

The methods and apparatus of the present invention in part developed asa result of, and in response to, certain general observations made withrespect to iontophoresis and iontophoretic devices. In this section ofthe discussion these general observations, and basic principlesconcerning them, are discussed. Detailed descriptions with respect toexperiments conducted, to develop the reported observations andprinciples, are provided in the experimental section at the end of thisdisclosure. General details and descriptions concerning methods andapparatus according to the invention, are provided in the next sectionof this detailed description.

1. Relationship Between Current and Drug Delivery for an IontophoreticSystem Involving Little or No Extraneous Ions in the Active Reservoir

Herein the term "extraneous ions" has generally been used to refer toions of the same charge (sign) as the material (for example drug or drugprecursor i.e. the target or therapeutic species) to be delivered fromthe active electrode, and present in the reservoir of the activeelectrode, when the target species is charged. For a positively chargeddrug species "D+", or a target species delivered from a reservoir of theanode, extraneous ions would be various cations (other than the targetspecies) in the solution of the active electrode, for example extraneousmetallic cations. All other cations, besides the target cation, will bereferred to herein as extraneous ions, regardless of whether or not theycarry the same absolute charge value.

The rate of delivery of the drug ion from the active electrode reservoirand across the skin membrane (in the absence of extraneous ions in thereservoir) is generally the sum of that amount of transfer which occursas a result of diffusion plus the amount of transfer (i.e.electrotransport) which occurs as a result of applied electromotiveforce (i.e., applied voltage). In this discussion diffusion processeswill generally be ignored as they do not concern the applied force, butrather are controlled by relative concentrations of the species onopposite sides of the skin barrier.

In general, the amount of transport which occurs as a result of appliedvoltage is directly proportional to the amount of current passingthrough the cell. Thus, in general, if the amount of current is doubled,the rate of transport due to the electromotive force is also doubled;see, for example, Padmanabhan, R. V. et al., "In vitro and In vivoEvaluation of Transdermal Iontophoretic Delivery of Hydromorphone", J.Controlled Release Vol. 11, pages 123-135 (1990), the disclosure ofwhich is incorporated herein by reference.

In practice, then, the amount of current can be utilized to control therate of drug delivery. This can generally be done in either or both oftwo manners: change in the potential (voltage) applied between theactive and ground electrodes; or, change in resistance to passage ofcurrent between the two electrodes. In practice, typically resistance toionic conduction between the two electrodes decreases, as theelectrolytic material in the electrode reservoirs begins to permeate theskin. That is, in practice there is observed a lower resistance tocurrent passing between the two electrodes, with passage of time. Thus,over a sustained period of time, for a typical iontophoretic system withlittle or no extraneous ions, constant rate of target ion delivery ortransport can be maintained with a lowering of voltage, at least over agiven range of concentrations of drug ion in the active reservoir,wherein the concentration is not modified greatly and is above athreshold level determined by physical/chemical properties of thetransported species and tissue through which transport occurs. Withrespect to this threshold level, reference is made to the principlesdescribed in the next section herein.

2. The Effect of Concentration of Drug Ions on Rate of Drug Delivery atConstant Current

In general, although rate of drug delivery is proportional to current,at a constant current the rate of drug delivery (R_(d)) is independentof drug concentration (i.e. target species concentration) in the activeelectrode reservoir, provided that the concentration is at least above athreshold level (and little or no extraneous ions are present); seePadmanabhan, R. V. et al. J. Controlled Release, supra.

3. Effect of Charge on Migrating Species

If charged at all, the migrating species may be of a variety of charges.For example, if the migrating species is a metallic cation, it could bea cation which has a +1 charge (for example potassium or sodium ions) orit could be a metallic cation which has a +2 (or some other) charge (forexample calcium or magnesium ions). In general, assuming otherwisesimilar mobility through the skin surface, for a given current thespecies having the greater charge will be less mobile. An explanationfor this should be apparent. In order to satisfy maintenance of aconstant current, twice as many +1 charged species would have to passthrough the skin, than would +2 charged species. Thus, in two differentsystems, a first system involving species of a +1 charge and a secondsystem involving species of a +2 charge, if a constant (and the same)current were maintained in each system (and mobilities were otherwisethe same), the system involving ions of a +1 charge would have twice therate of delivery, to maintain the same current. See, for example,Phipps, J. B. et al., Solid State Ionics, supra.

4. Effect of the Presence of Extraneous Ions in the Active ElectrodeReservoir

The presence of extraneous ions, as defined herein, in the activeelectrode reservoir will have a profound and significant effect on theabove related principles and observations. In general, this may be

understood by considering a hypothetical system. Assume for the moment asystem in which a constant current is maintained. The ionic transportneeded to maintain that current can be satisfied by any of theappropriately charged ionic species present in the active electrodereservoir being transported into the skin therefrom (or for that matterby ions of an opposite charge being transferred into the activeelectrode reservoir from the skin). Thus, transport of either the drugion (if charged) or the extraneous ions from the active electrodereservoir will satisfy the flow of current. Alternately stated, both the"target" species and (if ionic) the "extraneous" species in the activeelectrode reservoir will feel effects of the applied electromotiveforce. (However, if the target species and extraneous species arecharged with the same sign but to a different degree, they will feel adifferent force as described above.) Mobility of any given species willin part be a function not only of its charge, but also its molecularweight, size, charge density, etc. Thus, in general, the target speciesand the extraneous ions will not have the same mobility, (nor the samedelivery rate) for a given current.

The consequences of this may be understood from a hypothetical exampleinvolving further assumptions. Assume, for example, that the targetspecies to be delivered is a relatively large organic drug speciescarrying a +1 charge, for example hydromorphone cation (HM⁺) resultingfrom dissociation (ionization) of hydromorphone hydrochloride, i.e, thespecies is protonated hydromorphone. Assume further that the extraneousspecies present in the active electrode reservoir, along with thehydromorphone species, is a small highly mobile +1 charged species, forexample sodium ions. Under constant applied current, due to greatermobility, it can be expected that the rate of delivery of the extraneousions will be greater than the rate of delivery of the hydromorphone ion.This means that the concentration of the extraneous ions present in theactive electrode reservoir will drop more rapidly than the concentrationof the target species, hydromorphone.

Of course the rate of total ion transfer (i.e., rate of extraneous iontransfer plus rate of target species transfer) will remain generallyconstant, for a constant current, provided the threshold level of ionconcentration is exceeded, under the general principles discussed abovein paragraph 2 of this section. However, since the concentration ofextraneous ions is decreasing more rapidly than the concentration oftarget species, in time the relative rates of transfer of the two willchange. More particularly, the absolute rate of transfer of extraneousions, in time, will decrease and the relative rate of transfer of targetspecies will increase.

The above may be alternately stated, in a general form, as a principlethat the rate of delivery of any given species, under an applied voltagein an iontophoretic system, (electrotransport system in which thetransported species is charged) will be dependent on the fraction of thetotal transportable ionic species (i.e. target species plus extraneousions) represented by that target species (assuming all species have thesame charge, if they do not a factor for mobility difference due to acharge difference would be included in the formula). Thus, for a systemof mixed ions the rate of delivery of a target ion "T_(i) " in thepresence of extraneous ions "X_(i) ", under conditions of constantcurrent, will be dependent on the fraction [T_(i) ]/([T_(i) ]+[X_(i) ]).This fraction will be referred to herein as the "molar fraction" or"charge equivalent fraction", of the species T_(i) where [T_(i) ] is themolar (or charge) concentration of T_(i). and [X_(i) ] is the molar (orcharge) concentration of X_(i), in the active electrode reservoir. Theterm "molar fraction" as used herein will be understood to include acorrection for equivalents of charge. For example, [X_(i) ] as used inthe formula will be equal to 2 times the concentration of species X_(i),if X_(i) carries a charge value of 2, i.e., +2 or -2. The same will betrue for [T_(i) ]. It is noted that mobility of any species is not onlydetermined by charge state, but also molecular weight, hydrophilicnature and charge density, as well as degree of interaction with thetissue (skin).

A general principle which can be derived from above is that: if theactive electrode reservoir includes therein both a charged targetspecies and extraneous ions; and, if the target species and extraneousions do not possess identical mobilities, in time, under a given appliedvoltage (i.e., galvanostatic conditions), the rate of delivery of thetarget species will change. Whether it increases or decreases willdepend upon whether the target species is less mobile or more mobilethan the extraneous species. This principle will hold regardless ofwhether: the active electrode is operated as an anode or cathode; thetarget species is positively or negatively charged; the target speciesand the extraneous ions bear equivalent charges; the applied potentialis constant or varied in time; and, the current is constant or varied intime; etc. The reasons for this include the fact that the phenomenongenerally results from differences in mobilities between the chargedtarget species and the extraneous species.

The above asserted principle can be demonstrated experimentally. Thespecific experimental details for demonstration of this is providedhereinbelow, at Experiment 1; the data for which is reported in FIG. 1.In general, FIG. 1 provides the delivery rate in micrograms per hour ofa target species (hydromorphone cation) in an iontophoretic system underfour different circumstances. More particularly, four systems wereprepared in which the active electrode reservoir (the anode reservoir)initially included a selected concentration of hydromorphone, and aselected concentration of one of four extraneous ions, i.e., the fourexperimental runs each involved one of calcium (+2), magnesium (+2),potassium (+1) or sodium (+1) ions, as the extraneous ions. Throughoutthe experiment, a constant current of approximately 1 mA (milliamp) wasmaintained. As can be seen from FIG. 1, in each instance the rate ofhydromorphone delivery, under conditions of constant current, was foundto increase in time. The reason for this, again, is the generalprinciple enumerated above that:

(a) Since the smaller extraneous ion species (whether Ca⁺², Mg⁺², K⁺¹ orNa⁺¹) is more mobile than the relatively large organic hydromorphonespecies; and

(b) Since the rate of transfer of the drug species (hydromorphone),under constant current, is a function of the concentration of the targetspecies divided by the charge concentration of the target species plusthe charge concentration of the extraneous ions, then,

(c) as the concentration of the extraneous ions [X_(i) ] decreases morerapidly than the concentration of the hydromorphone ions [T_(i) ]described below, the ratio represented by the function (for molarfraction or charge equivalency fraction) increases, and thus the rate ofdelivery of the target species increases. (In other words, in time themolar fraction of T_(i) increases and the delivery rate (R_(d)) of T_(i)also increases.)

It is noted that for the experimental data reported in FIG. 1, theincrease in the rate of the hydromorphone for each of the four systemswas linear. This could be expected for a system in which throughout theexperiment both the concentration of the target ion and the extraneousions is maintained above the threshold level.

5. Problems Resulting from the Above General Principles and Observations

The above general principles and observations present a significantproblem, to practical application of iontophoresis techniques. If theactive electrode reservoir were maintained completely free of extraneousions, generally no problem would be presented. However, as explainedabove, generally this cannot be readily accomplished at least for thereasons that: the presence of extraneous ions may be desirable due tothe need, for example, for buffered systems, systems involving additivessuch as antibacterial agents etc., systems wherein biocompatability isfavorably influenced by introduction of selected ions; and, the generaldifficulty of obtaining extraneous ion-free electrode reservoirs. Thus,while the basic principles from the Phipps et al. U.S. Pat. Nos.4,747,819 and 7,744,787 could be applied to avoid further generations ofextraneous ions during the iontophoretic process itself, developingextraneous ion-free reservoirs in the first instance, can be relativelydifficult or for other reasons undesirable.

On the other hand, if the active electrode reservoir is not extraneousion-free, precise or satisfactory control over drug delivery rate can bedifficult, if not impossible, to achieve. Further, and in particular,for such a system it may be desired that the drug delivery rate bemaintained constant, which, for conventional systems, has been nearlyimpossible to achieve. For example, in a system in which the extraneousions are more mobile than in the drug ion, under a constant appliedcurrent, delivery rate of the drug ion will increase in time, asindicated above. The rate of delivery of the drug ion could bedecreased, to counterbalance this, by decreasing the applied voltage(i.e., decreasing the current). A problem with this, is that any changesin the current from the electrode will not only effect the rate ofdelivery of the drug ion, but also the rate of delivery of theextraneous ions as well, so the imbalance will be regenerated. Thus,continual modification in the amount of current would be necessary, toobtain precise control over the rate of delivery of the therapeuticagent. Also, it may be found that control over the current sufficient tomaintain a constant rate for and extended period of time may beimpossible to achieve, due to limits based on the highest currentacceptable and lowest current acceptable to the patient under theconditions of iontophoresis. Also, with multiple variables such asconcentration of extraneous ions, concentration of the therapeutic ions,etc. being involved, calculation of appropriate levels for precisecontrol may be difficult. Of course if a huge excess (relative to drugion) of extraneous ions were used, the differences in mobility would beless important; however, the molar fraction of the target ion would beso low that iontophoresis would be inefficient. Also, if the activeelectrode reservoir were constantly replenished with fresh electrolyte(i.e., it were not a "closed" reservoir") the molar fraction of Ti wouldbe constant; however, such a system would be cumbersome andinconvenient.

B. General Methods of the Present Invention

The present invention, inter alia, concerns methods applicable to obtainselective control over delivery rate of a target ion or therapeutic ion,T_(i), in the presence of extraneous ions, X_(i), in an active electrodereservoir. The methods may also be used to maintain a selected ionspecies at a desired concentration, to advantage, for example to enhancetarget species stability or biocompatibility. The methods of the presentinvention are generally referred to herein as methods for controlledenvironment electrotransport.

More specifically, the methods are particularly well adapted for use inassociation with a "closed" reservoir system, i.e., a reservoir systemwhich is initially prepared with a particular volume of ion containingsolution (or gel) where that solution or gel is not continuallyreplenished from an essentially unlimited supply. A basic step inapplications to the methods is to provide for adjustment in the presenceof selected ions in the active electrode reservoir, in time, in aselected manner.

1. A Basic Step of Certain Preferred Applications: Selective Generationor Removal of Extraneous Ions to Desirably Effect [X_(i) ] DuringIontophoresis

When conducted according to the present invention, preferred methods ofiontophoresis will include steps for selected modification in thepresence of extraneous ions in the active electrode reservoir.Adjustments in the presence of extraneous ions may take either of twoforms, depending upon the system: (a) addition of extraneous ions to thesystem; and, (b) removal of extraneous ions from the system. In general,this may be done to obtain (or maintain) a desired molar fraction oftarget ion, T_(i), during the iontophoresis or for maintenance ofconstant cell conditions, for example pH. That molar fraction of T_(i)may be maintained as a constant, for a constant rate of delivery ofT_(i), or increased or decreased as desired.

(a) Addition of Extraneous Ions to the Active Electrode Reservoir

It will be desirable to control the active electrode reservoirenvironment by addition of extraneous ions to the active electrodereservoir, either continuously or periodically throughout theiontophoretic operation (i.e., during passage of current through theactive electrode reservoir and during electrotransport), under at leastany of three conditions: (i) extraneous ions in the reservoir are moremobile than the target or therapeutic ion, and thus their continualdepletion is leading to an undesired increase in rate of target iondelivery; (ii) under conditions of operation of the iontophoretic systemextraneous ions in the active electrode reservoir are being depleted bymeans other than electromotive transport (through the skin) therefrom,again leading to an undesired rate of increase in delivery of targetions; or, (iii) regardless of the method of loss, extraneous ions arelost and it is desired to maintain their presence constant, an exampleof this latter being constant pH. Any of these may be referred to by thegeneral phenomenon that it may be desirable to add, either continuouslyor periodically, extraneous ions to the active electrode reservoirthroughout the operation of iontophoresis, in response to what wouldotherwise be an unacceptable depletion or rate of depletion, in time, ofthe concentration of extraneous ions within the active electrodereservoir.

(b) Removal of Extraneous Ions from the Active Electrode Reservoir

Similarly, it may be desirable to selectively remove extraneous ionsfrom the active electrode reservoir, either continuously or periodicallyduring the conduction of iontophoretic process, under at least any ofthree conditions: (i) the target ion is more mobile than the extraneousions, thus the rate of depletion of the target ion is dropping in timeas its concentration reduces, rapidly, relative to the concentration ofextraneous ions; (alternately phrased the molar fraction of T_(i)decreases in time); (ii) electrochemical reactions within the activeelectrode reservoir lead to an undesirable increase in the concentrationof extraneous ions in time again leading to a decrease in the rate ofdelivery of T_(i) ; or, (iii) regardless of how, [X_(i) ] is increasing,and it is desired that it be maintained constant, again an example ofthis letter being constant pH which can be affected by removal ofhydronium ions (H⁺) or hydroxyl ions (OH⁻).

2. The Preferred Method of Modifying the Presence of Extraneous Ions inthe Active Electrode Reservoir: Operation of a Second Electrode Therein

In preferred applications of the present invention, the presence ofextraneous ions in the active electrode reservoir is modified eitherperiodically or continuously throughout the electrotransport process(i.e., while electrotransport into a subject of the process isconducted), through operation, in the active electrode reservoir, of asecond or secondary electrode system. That is, in addition to theprimary electrode system of the iontophoresis system, in contact withthe active electrode reservoir and selectively operated duringiontophoresis, a secondary electrode system is provided. The secondaryelectrode system can be operated, as desired, to selectively effectextraneous ion presence and concentration. Of course, operation of thesecondary electrode system may also cause electrotransport in somesystems.

(a) The Addition of Extraneous Ions

A secondary electrode system capable of producing extraneous ions couldbe placed in the active electrode reservoir, and continuously orperiodically operated to generate extraneous ions, providing a feed tothe active electrode reservoir. For example, assume that the appropriateextraneous ion for introduction to the active electrode reservoir, toreplace some depleting extraneous ions during the iontophoresis process,were hydronium ions. If the secondary electrode placed in the activeelectrode reservoir of the iontophoresis process was one that wascapable of producing hydronium ions, selectively, when a current ispassed therethrough, it could be operated either continuously orperiodically, to generate hydronium ions replacing those lost. In thealternative, or in addition, if the extraneous ion being lost from theactive electrode reservoir during iontophoresis were sodium ions, asodium tungstate intercalation-type electrode could be provided as asecondary electrode, and operated as an anode. If the extraneous ionbeing depleted during operation of the iontophoresis cell were Cu⁺², acopper electrode operated as an anode, capable of releasing Cu⁺² uponpassage of current therethrough, could be provided in communication withactive electrode reservoir and periodically or continuously operated toproduce extraneous ions. It will be understood that the three examples(hydronium ion, sodium ion and copper ion generation) given were meantto be representative and not limiting.

In general, it will not always necessarily be desirable to generateextraneous ions at the same rate they are depleted, due to transport.That is, it will not necessarily always be desirable to maintain [X_(i)] constant. A reason for this is that if [X_(i) ] were constant, and[T_(i) ] were decreasing, then the R_(d) (rate of delivery) of T_(i)would decrease; and R_(d) for X_(i) would continually increase. Thus,the efficiency of iontophoresis would reduce in time. Of course in someinstances it may be desireable to maintain [X_(i) ] constant, forexample a relatively constant pH might be maintained for patient comfortand system biocompatability or to maintain stability of some species inthe reservoir. The concept of biocompatibility is generally discussed inMolitor, H. et al, Am. J. Med. Sci., Vol. 198 pp 778-785 (1939), thedisclosure of which is incorporated herein by reference.

The electrode system for adjusting or modifying extraneous ion presenceshould be a different electrode system than (or a system operated todifferent effect from) the primary electrode system for theiontophoresis. That is, in applications of the present invention twodifferent electrode systems are provided in electrical contact with theactive electrode reservoir, one of which is for selective operation toaffect the presence of X_(i) independently of T_(i). Details concerningthis are provided in apparatus discussions below.

Herein when it is said that the secondary electrode system is"different" from the primary electrode system, it is meant that theeffect of electrochemical reactions generated thereby, on the ioniccontent of the active electrode reservoir, are different, i.e., aneffect in addition to (or as an alternative to) mere electromotiveeffect, and different from the electrochemical effect of the primaryelectrode, is provided by the secondary electrode. The particular anddesired effect of each will depend upon the system of interest, witheach being chosen to perform in a selected manner to achieve the desiredeffect. In some systems both electrode systems may comprise identicalmaterials, one system being operated as an anode, the other as acathode. Since their effects on the ionic content of the reservoir wouldbe different, they would be "different" systems according to the abovedefinitions.

(b) Removal of Extraneous Ions from the Active Electrode Reservoir

In contrast to the methods of the previous section, under somecircumstances it may be desirable to operate a secondary electrodesystem in communication with the active electrode reservoir in a mannersuch that extraneous ion presence is reduced. For example, if it isdesirable to remove Cu⁺² from the active electrode reservoir, in orderto maintain a desired delivery rate of target species, a secondaryelectrode system capable of removing Cu⁺² from the active electrodereservoir could be used. An example of this would be to operate a copperelectrode therein as a cathode, plating copper ions from the activeelectrode reservoir thereon as copper metal. If the extraneous ion werea sodium cation, its presence could be reduced by operation of a sodiumtungstate electrode as a cathode. These examples will be understood togenerally exemplify methods of the present invention whereby extraneousion concentration is reduced.

3. Alternate Method: Operation of the Secondary Electrode System toModify Concentration of the Target Species

It will be apparent that if the important ratio to control the rate ofdelivery of the target species is the concentration of the targetspecies ion relative to total ion content (i.e. molar ratio of targetion), then control over that ratio can be maintained by either:modifying the presence of extraneous ions, as described in section B2above; or, by modifying the presence of target ions; or, both. For manysystems, modification of the concentration of target ions will be lessdesirable, as it would concern modifying the presence of the key speciesto the therapeutic process. However, in some applications it may bedesirable. For example, if the concentration of extraneous ions isreducing, in time, at a rate greater than the change in concentration ofthe target species, leading to the tendency for an increase in the rateof target species delivery across the skin barrier, the ratio of [T_(i)] to ([T_(i) ]+[X_(i) ]) could be modified by reducing, eitherperiodically or continuously, [T_(i) ], without transport, to maintainthe ratio at a desired figure. A variety of manners of operations of thesecondary electrode could be utilized to accomplish this depending onthe system. For example, if the target species were a metal cation, thesecondary electrode could be operated as a cathode selected for removalof that particular species from the system. If the target species were aparticular organic cation, the secondary electrode could be operatedeither in a manner to produce an anion for that organic cation, which,in combination with the organic cation, forms an insoluble precipitatein the reservoir, thus effectively reducing concentration of T_(i)available for electromotive transport; or, in a manner which destroys(or otherwise renders inactive) the organic species, again effectivelyreducing concentration of T_(i) available for transport.

4. Operation of the Secondary Electrode System as an Anode or Cathode

Whether the secondary electrode system is operated as a cathode or anodedepends, primarily, on the nature of the electrochemical reactions to beprecipitated thereby, and not whether the primary electrode system inthe same reservoir is itself operated as an anode or cathode. That is,if the primary electrode system is operated as an anode, the secondaryelectrode system may be selectively operated as either an anode orcathode, depending upon the reactions to be initiated thereby. Inaddition, if the primary electrode system is operated as a cathode, thesecondary electrode system may be operated as either an anode or acathode, again depending upon the reactions to be precipitated thereby.If the secondary electrode system is operated analogously to the primaryelectrode system (i.e., both as anode or both as cathode) then thecompanion electrode for each will be the remote, ineffective, or groundelectrode of the iontophoresis system. If, on the other hand, thesecondary electrode system is operated in an opposite manner withrespect to current flow from the primary electrode system (i.e., one asan anode and one as cathode) and both are operated at the same, timethen the secondary electrode system, will, at least in part, involvecurrent flow with the primary electrode system (i.e., between theprimary and secondary electrode systems, the direction of current flowdepending on which is the anode).

What is generally required is: that the secondary electrode system beprovided out of "direct" electrical contact with the primary electrodesystem, i.e. the secondary electrode should be isolated (spaced) fromthe primary at least by the electrolyte material of the reservoir; and,that the secondary electrode system be provided in appropriateelectrical communication with the electrolyte solution (gel or gelmatrix) of the active electrode reservoir. Specific arrangements foraccomplishing this are described herein below, where preferred apparatusis described.

5. Relative Amount of Current Flow Through the Primary Electrode Systemand the Secondary Electrode System

Herein, the term "primary electrode system" has been utilized to referto the electrode system which in general, would have defined theelectrotransport system of concern if the system were conventional; and,the term "secondary electrode system" has been utilized to refer thatelectrode which is selectively operated to selectively adjust thepresence of, or relative concentrations of, target ions and/orextraneous ions in the active electrode reservoir (without transport orin addition to transport). This may be done, for example, in response toundesired changes in ionic content of the reservoir, for example thoseprecipitated by operation of the primary electrode system. The term"undesired changes" in this context generally includes within its scopechanges in the molar ratio which in some undesirable manner affects rateof delivery (Rd) of the target ions, and changes that undesirably affectstability of the reservoir, patient comfort or system biocompatibility.The term "without transport" in this context means a change in ionpresence accomplished without transport of the ion through to thesubject of the iontophoresis; i.e., without transport across the skin.By the use of the terms "primary" and "secondary" in this manner, thereis no intention to suggest that there is some necessary or preferredrelative amount of current to be passed through the two electrodesystems. That is, in operation of electrotransport apparatus, accordingto the present invention, the majority of the current may be carried bythe primary electrode system, or it may be carried by the secondaryelectrode system, or the ratio or relative amounts may change during theoperation. In general, this will depend upon the amount ofelectrochemical change that must be precipitated by the secondaryelectrode system in order to achieve the desired relative concentrationsof T_(i) and/or X_(i) in the system, or to achieve the desired effect on[T_(i) ] and/or [X_(i) ]. In some systems it may be appropriate to haveno current flow through the primary electrode system, while thesecondary electrode system is operated. This will, in part, depend uponat least: the effect of the secondary electrode system on transport;and, the need for, or desirability of, maintenance of constanttransport.

It should also be noted that the terms "primary electrode system" and"secondary electrode system" are not necessarily utilized to refer toelectrodes in the singular. That is, the primary electrode system maycomprise a single electrode or a plurality of electrodes; and, thesecondary electrode system may involve a single electrode or a pluralityof electrodes. Further, electrodes in addition to the primary electrodesystem and the secondary electrode system may be utilized in somesituations.

6. A Preferred Application: Maintenance of a Constant Rate of T_(i)Delivery (R_(d).sbsb.Ti)

In many applications of iontophoresis where extraneous ions are presentin the active electrode reservoir, it may be desirable to merelymaintain the rate of delivery (R_(d)) of the target or therapeutic ion,T_(i), as constant. If, as explained for hypothetical above, the targetion T_(i). is less mobile than the extraneous ion X_(i), underconditions of constant current, in time, the R_(d) of T_(i) willincrease because of the rate of depletion of the more mobile extraneousions is greater than the rate of depletion for the less mobile targetions. That is, with time the molar fraction of T_(i) increases. For sucha system, it may be desired to maintain the rate of delivery of thetarget ions constant. This can be readily achieved by, in time,replacing the extraneous ion X_(i) at a rate sufficient to maintain themolar ratio of T_(i) constant. This will be a rate slower than the R_(d)of X_(i), since [T_(i) ] is constantly reduced, in the closed reservoirsystem. Maintenance of relatively constant molar fraction of T_(i) canbe accomplished, for example, by operation of the secondary electrode,on a periodic or continuous basis, with sufficient current to produceextraneous ions in the system as necessary. Herein, when it is said thatthe molar fraction of a species such as T_(i). is maintainedsubstantially or relatively constant, it is meant that it is preferablymaintained within about 30.0% of its original or a preselected value,more preferably within about 10.0%, throughout the iontophoresisprocess. In general, the need to maintain the molar fraction of a targetspecies within some specified value will be related to the therapeuticindex of a species. It will be understood that the present invention iswell suited to applications wherein a high degree of control isnecessary.

In general, a constant rate of delivery of T_(i) can be maintained insome systems without replacement of the very same extraneous ions as arelost, if the extraneous ions that are put into the system haveapproximately the same mobility, relative to the target ion T_(i), as dothe original extraneous ions in the system. For example, if the originalextraneous ions in a system are sodium ions, and the original target ionin the system is a large, relatively immobile, organic ion such as thehydromorphone ion, the extraneous ion put into the system with time, bythe secondary electrode, could be a sodium ion, but it also could be asimilarly charged and similarly mobile ion.

Further, in some applications a constant rate of delivery of thetherapeutic or target ion T_(i) can be maintained even if the lostextraneous ions are replaced with extraneous ions of substantiallydifferent mobility, provided the current and/or rate of introduction ofextraneous ions is adjusted to accommodate the different mobilities. Forexample, if an extraneous ion of a first mobility is being replaced(partially or completely), by operation of the secondary electrode, byan extraneous ion having twice the mobility, and if the rate of deliveryof T_(i) is to be maintained constant, then the rate of introduction ofthe new extraneous ion by means of operation of the secondary electrodeshould be provided at approximately one half of the rate of the loss ofthe initially present extraneous ion.

It will be understood that one problem with replacing (partially orcompletely) extraneous ions with different extraneous ions, is that thetotal transferrable ion pool in this system becomes modified in time, asit will eventually comprise a mixture of the originally presentextraneous ions and secondarily introduced extraneous ions. Thus,operation of the secondary electrode after the initial introduction mayhave to take into account the plurality of extraneous ions present.There is no apparent reason why this cannot be accomplished, however, ifappropriate model systems and/or calculations and/or methods ofdetection are used.

7. A Preferred Application: Maintenance of a Constant Concentration ofan Extraneous Ion

In some applications it may be desirable to maintain a constantconcentration of an extraneous ion. This is the case, for example, if aconstant pH is desired (e.g. to facilitate: drug stability; drug chargestate, for example if the target ion is a polypeptide; and/orbiocompatibility). In such circumstances, the secondary electrode can bechosen and operated to replace (or remove) hydronium or hydroxyl ions,as necessary, at the same rate they are depleted (or added) to thereservoir, by other means. Thus, constant pH could be maintained in asystem in the absence of a pH buffer. This will be particularly usefulin those situations in which the buffer could have deleterious effectson target ion delivery.

8. A Preferred Application: Maintenance of a Constant Total CurrentPassing Through the Subject

In many systems it may be desirable to maintain a constant total currentthrough the subject, during the electrotransport process. This may, forexample, facilitate subject comfort and avoidance of undesirable sideeffects. It may also be convenient, in terms of chosen apparatus. Ifsuch an effect is desired, it may be necessary to provide appropriateelectronic control of primary and secondary electrode systems, to effecta balance. For example, if operation of the secondary electrode systemwould otherwise involve an increase in current passing through theactive electrode reservoir (and through the subject), its operation maybe matched by a decrease in the current provided through the primaryelectrode system. Such a balance can be readily achieved with electroniccircuitry presently available.

Herein, when it is said that an electrotransport system is operated at a"constant current" regardless of whether or not the secondary electrodesystem is in operation, it is generally meant that the current passingbetween the active electrode reservoir and the inactive electrodereservoir, i.e., through the subject, is preferably maintained at aselected constant value, plus or minus about 30.0% of that value. Morepreferably it is maintained at a constant value plus or minus less thanabout 10.0% of that value, throughout the process.

9. Determining the Rate at Which the Presence of Target or TherapeuticIons T_(i), or the Presence of Extraneous Ions X_(i), Should beSelectively Modified by the Secondary Electrode (Either by Increase orDecrease in Presence of X_(i), or by Increase or Decrease in Presence ofT_(i))

In general, certain preferred applications according to presentinvention involve selective operation of the secondary electrode in apreferred manner, in order to achieve the desired effect on the molarratio of the target ions. In preferred, controlled, applications, then,it is essential to know what level of operation the secondary electrodeis appropriate to achieve a desired effect. Guidance in this may beaccommodated in either of two general manners: utilization of systemsbased upon model systems; or utilization of a feedback sensorarrangement in the active electrode reservoir.

(i) Model Systems

In typical applications, the electrotransport system will involve targetspecies and extraneous ions, and concentrations of those species andions, which will have been modeled and studied for that particularsystem, when operated under a selected current with respect to aselected type of subject. Thus, from model studies, it will be known towhat extent, and under what conditions, the secondary electrode systemshould be operated. Operation of an electrotransport system with asubject, with known parameters and variables from models, is a matter ofproviding appropriate control of the various electrodes, throughout theiontophoresis procedure. This could be accomplished, for example,through a preprogrammed control system.

(ii) Use of a Feedback Sensor

In other systems, it may be desirable to adjust the operation of theelectrodes, most notably the secondary electrode, in direct response todetected changes in the environment (for example ion content) of theactive electrode reservoir. Such a system will be referred to herein asa "feedback" system and the means for detecting the change in the ioncontent of the active electrode reservoir will generally be referred toherein as the "feedback sensor" means or sensor means. The feedbacksensor or sensor means may be utilized merely to detect a change, withthe control system for the primary and secondary electrodes programmedto make a particular response in operation of the electrodes in responseto a given detected change; or, a continual feedback system may beutilized, wherein the electrodes are operated by a control system tocontinually adjust, in order to maintain the feedback sensor measurementat a preselected value.

A variety of sensor means may be utilized, and in general, the meanschosen will depend upon the particular electrical system andelectrochemical reactions involved. For example, if hydronium orhydroxide ions are the extraneous ions content of concern, the feedbacksensor may be a pH sensor of any variety of types. Other sensor systemsor types of sensors which may be utilized in various applications of thepresent invention include: total inorganic ion concentration sensors;total organic ion concentration sensors; ion selective sensors; opticalsensors; conductivity sensors; etc. This list is not meant to beexhaustive, but rather exemplary of the various methods and techniquesthat may be utilized to detect either extraneous ion concentration,target ion concentration, or some other chemical or physical parameteruseful in determining desired adjustments in operation of the primaryand secondary electrode systems, to achieve a selected effect.

10. Applications When the Target Species is Not Charged

From the above descriptions, applications of methods according topresent invention in systems wherein electrotransport is conducted, butthe target species is not charged, will be understood. For example,electro-osmosis may involve utilization of an electrotransport device inorder to transport a charge species, to facilitate transfer of anuncharged target or therapeutic species. Such systems may involveapplications of the general principles described above, however, thespecies being transported for therapy is not itself charged.Nevertheless, controlled environment processes may be desirable, andthus a primary electrode system and secondary electrode system operatedgenerally as described above may be utilized. More specifically, thesecondary electrode system may be utilized to control extraneous ionpresence (or the presence of the ion being transported in order tofacilitate transfer of the therapeutic species), to maintain constant pHor conductance, or to in some other manner desirably effect the activeelectrode reservoir.

11. Applications to Render Species Inactive, for Disposal

In some systems, the active or target species may be a controlled anddangerous substance, such as a narcotic. Disposal of the reservoir,after use, may be a problem for such systems. However, if the reservoircontains two selectively operable electrode systems therein, a selectedcurrent or potential can be applied between them which is sufficient todegrade or otherwise render the drug inactive, at termination of thedelivery process.

More general principles in detail concerning application and methodsaccording to the present invention will be understood from the followingapparatus descriptions.

C. General Apparatus Usable and Applications of the Present Invention

1. General Electrode Construction

In FIG. 2, schematic representation is presented of an arrangementutilizable to effect methods generally described above, according to thepresent invention. In FIG. 2 an overall electrotransport drug deliverysystem 5 is depicted. This system 5 includes an active electrodereservoir 6 and an inactive electrode reservoir 7, both provided inelectrical contact with a skin surface 10 of a subject to be treated. Ingeneral, active electrode reservoir 6 includes therein an electrolytepool in the form of a gel or gel matrix 15 containing ionic drug species16 to be delivered, as well as extraneous ions 17. The inactive orground electrode reservoir 7 includes therein a gel or gel matrix 20including sufficient electrolytes therein for passage of currenttherethrough, for example saline solution.

Both reservoirs 6 and 7 are provided in electrical communication withsurface 10, retention being preferably achieved by means ofskin-compatible pressure sensitive biomedical adhesive layers 25 and 26respectively. In some instances a conductive adhesive provided directlybetween reservoirs 6 and 7, and skin surface 10 may be used.

A primary electrode system for arrangement 5 is illustrated generally at30. The primary electrode system 30 generally comprises a grid 31 of aselected electrode material in electrical communication with powersource 35. In FIG. 2, this is illustrated by means of communicationlines 36 and 37, with power from power source 35 passing through acontrol module 40, referred to in more detail below. The control module40 includes means for adjusting and controlling the amount of currentprovided to grid 31.

In general, grid 31 is provided in intimate contact (i.e. electrical orelectrically conductive contact) with gel matrix 15, so that as currentis applied to the grid 31, electromotive force is applied to ions, forexample the drug species 16, (if charged) and the extraneous ions 17,supported in the matrix 15, driving same into the skin surface 10.

Still referring to FIG. 2, a companion electrode 45 to the primaryelectrode 31 is provided in the inactive or remote electrode reservoir7. Electrode 45 provides for completion of the electrical circuit uponpassage of current through the skin 10. Electrode 45 is in communicationwith power source 35 by means of communication line 46.

As thus far described, arrangement 5 may be a conventional iontophoresiselectrode system: with either of electrodes 30 or 45 being an anode andthe other being a cathode; with power source 35 being an appropriatesource of current; and, with control arrangement 40 providing forcurrent level control through the system. Arrangement 5, however,differs from conventional arrangements by means now described.

Still referring to FIG. 2, active electrode reservoir 6 of arrangement 5includes therein a secondary electrode system 50. Electrode system 50 isdifferent from system 30, i.e. when operated its effect on the ioncontent of reservoir 6 is different from the effect of electrode system30. The specific effect selected will depend upon the specific effectneeded, in application of the general methods described above. Electrodesystem 50 includes an electrode 51 in intimate (i.e. electricallyconductive) contact with reservoir material 15. Current to or fromelectrode system 50 is provided by means of communication wire 55, fromcontrol unit 40.

As described thus far, control unit 40 can be utilized to controloverall current between active electrode reservoir 6 and inactiveelectrode reservoir 7, i.e., current passing through the skin 10 ofsubjects being treated. Further, control unit 40 can be utilized toselectively control current through either and both of primary electrodearrangement 30 and secondary electrode arrangement 50, as well as theground or inactive electrode 45. Appropriate circuitry means for controlunit 40 to accomplish this may be through conventional circuitry meansusing principles within the knowledge of persons in the art of designingcontrol circuits for current flow.

As previously indicated, control unit 40 may include microprocessormeans to control relative current passing through primary electrodearrangement 30 and secondary electrode arrangement 50 pursuant to apreprogrammed schedule, and/or it may include means for adjustment ofcurrent through either or both of primary electrode arrangement 30 andsecondary electrode arrangement 50, in response to feedback provided bya sensor arrangement within active electrode reservoir 6. Referring toarrangement 5 of FIG. 2, sensor arrangement 60 is shown located withinreservoir 6, preferably immersed within gel 15 near an end region 61 ofgel 15 located adjacent the skin surface 10. That is, in general themost important region of the entire reservoir 6 in which to determineion presence is the region in the immediate vicinity of the skin surface10, and it will in general be preferred to position the sensorarrangement 60 for detecting ion presence in that location.

The sensor 60 may be in a variety of arrangements, depending on theparticular system utilized. For example, it may be a pH sensor or an ionselective electrode, as needed. Sensor 60 is shown in communication withcontrol means 40 by communication arrangement 65, i.e., a wirearrangement or the like. It will be understood that for a systemutilizing sensor 60, control means 40 may be provided with appropriatecircuitry and processing arrangements so that in response tomeasurements taken by sensor 60 current through electrode arrangement 30and electrode arrangement 50 could be adjusted to achieve a desiredmodification in the extraneous ion content of active electrode reservoir6.

In general, the schematic of FIG. 2 will be appropriate: regardless ofwhether or not the primary electrode arrangement 30 is operated as ananode or a cathode; regardless of whether or not the secondary electrodearrangement 50 is operated in the same manner as the primary electrodearrangement; and, regardless of whether more current is carried by theprimary electrode arrangement than the secondary electrode arrangement,or vice versa. Further, the schematic is not intended to indicate therelative locations of the primary electrode arrangement 30 and thesecond electrode arrangement 50 in all preferred embodiments. Asexplained previously with respect to this, what is generally requiredis: that the two not be in direct contact with one another so thatcurrent can pass directly therebetween without passage through the gelor gel matrix 15; and, that both be provided in intimate (i.e.electrically conductive) contact with the electrolytic gel or gel matrix15.

A schematic arrangement generally representing a typical electrodearrangement is also depicted in FIG. 3. The arrangement of FIG. 31 itwill be understood, is generally according to the principles of theschematic of FIG. 2. Referring to FIG. 3, schematically depicted incross section are two generally circular electrode-containing sections100, 101 mounted within an electrotransport drug device 105. Device 105includes an outer shell or housing 106 defining first and secondcavities 107, 108. Preferably, housing 106 is formed from a flexible,non-conductive material that can be comfortably and conveniently appliedto an iontophoresis subject. Preferred material is a self-supportingmedical-grade polyethylene foam, such as those available for 3MCorporation, Medical Products Division. For the arrangement shown,cavity 107 defines and retains therein the active electrode and activeelectrode reservoir, and cavity 108 defines and retains therein thecompanion "indifferent" or ground electrode and ground or inactiveelectrode reservoir.

In a typical preferred application, perimeter surfaces 115 of housing106 include thereon a skin-compatible pressure-sensitive biomedicaladhesive 116, (preferably non-conductive) intended to hold the electrodestructure 105 in place on a subject's skin during iontophoretic drugdelivery. Alternatively, the iontophoresis device may be held in placeby other means, for example, a strap or tape, in which instance adhesivefields such as adhesive fields 116 may not be needed. As previouslysuggested, conductive skin adhesive can be used between the reservoirsand the skin. In general, delivery from arrangement 105 is downwardlyinto the skin, generally along the direction indicated by arrow 120 fromcavity 107.

Referring still to FIG. 3, cavity 108 includes therein an electrolytemedium, typically electrically conductive gel or gel electrolytesolution 125, appropriate for carrying current from the skin surface toan electrode contained therein. In the arrangement shown in FIG. 3, aninactive or ground electrode arrangement 130 is depicted comprising aconnector 131 attached to a wire 132. The connector 132 is shown inelectrical communication with a grid 133 for dispersion of current (orcurrent pickup) throughout a horizontal cross-section of chamber 108 forefficiency. The grid 133 should be well immersed within matrix 125 toensure good electrical conductivity. A wide variety of materials may beutilized as a gel or gel matrix (in either reservoir), including agar,polyvinylpyrrolidone gels and those matrices described in U.S. Pat. No.4,820,263, incorporated herein by reference. The gel or gel matrix maybe a composite (layered) system.

Attention is now directed to chamber 107, which defines and containstherein the active electrode reservoir 140. Active electrode reservoir140 includes therein gel matrix 141, which includes therapeutic agents142 for delivery along path 120 into the skin of a subject. The gelmatrix 141 may be generally as described for gel matrix 125, except ofcourse it is at least loaded with the target ionic species, or precursorfor the target species, to be delivered into the patient. The primaryelectrode reservoir 140 includes immersed therein the primary electrodearrangement 155 comprising electrically conductive contact 156 anddispersion grid 157. Electrical contact from a control unit and a powersource to contact 155 is provided by means of wire 161.

Thus far, the arrangement described may be generally according toconventional iontophoretic drug delivery systems, such as the onedescribed in U.S. Pat. No. 4,747,819 to Phipps et al., incorporatedherein by reference.

A major difference between the arrangement of FIG. 3 and those ofconventional systems is that active electrode reservoir 140 alsoincludes therein a secondary electrode arrangement 170. Secondaryelectrode arrangement 170 comprises a contact 171 in communication witha dispersion grid 172. Electrical communication from a power sourceand/or control unit or the like to contact 171 is provided by means ofwire 173.

Direct electrical contact (i.e., touching contact) between electrodearrangement 155 and secondary electrode arrangement 170 is avoided bymeans of non-conductive section 180 therebetween. In FIG. 3, each grid157 and 172 is imbedded in the foam of the construction, so they aremaintained spaced apart by a non-conductive portion 180 of thatconstruction. Due to the porous nature of grids 157 and 172, it will beunderstood that both are in intimate contact with gel matrix 142, andthus both can influence the chemical content thereof and migration ofspecies therethrough.

The arrangement of FIG. 3 also includes therein a sensor arrangement 190for detecting or sensing the nature or change in nature of the gelmatrix 142 during electrotransport. Sensor arrangement 190 includes asensor 191, which is inserted within gel matrix 142, and a communicationarrangement 192 (for example a wire circuit) for communication withcontrol means or the like. Preferably, sensor 191 is oriented in aportion of gel matrix 142 substantially adjacent the skin surface of apatient being treated, i.e., sensor 191 is oriented just within cavity107 from peripheral surface 115. Advantages derived from this arediscussed above.

Control means and power source for complete operation of the arrangementof FIG. 3 are generally shown at 193 and 194 respectively. For thearrangement of FIG. 3 the control means 193 and power source 194 areimbedded within construction 115. In some applications they may beremote therefrom. In FIG. 4, a top plan view of the arrangement 105illustrated in FIG. 3 is shown.

2. The Construction of the Primary Electrode

As previously explained, the primary electrode arrangement may beconstructed for operation as either a cathode or an anode, dependingupon the particular application of the principles of the presentinvention. In general, again depending upon the particular application,it may be constructed for operation as: an "inert" or "electrolysis"electrode; a sacrificial electrode; a plating electrode; and/or, anintercalation-type (or insertion-type) electrode. Herein, in thiscontext, the phrase "inert" or "electrolysis" electrode, and variantsthereof, is meant to refer to an electrode which does not itselfparticipate in chemical change in the electrolyte solution duringoperation, but is used as an electrode during operation to generateeither hydronium or hydroxide ions in the solution via typicalelectrolysis processes. Examples of such electrodes are platinum andcarbon electrodes. The term "inert" electrode also includes an electrodewhich causes oxidation/reduction reactions, without plating,intercalation, insertion or sacrifice, to effect the electrolyte contentof the reservoir. Herein, the term "sacrificial" electrode is used torefer to an electrode which is operated to release ions into theassociated electrode reservoir during operation at the sacrifice (i.e.,non-replaceable expense) of the electrode, for example, a wide varietyof metal electrodes operated as anodes would be sacrificial electrodes,typical examples being silver, zinc and copper electrodes. The term"plating" electrode in this context is used to refer to an electrodewhich is operated to plate ionic species in solution at a surfacethereof. An example of such an electrode would be a copper electrodeoperated as the cathode in a solution containing copper ions. Duringsuch operation copper ions will be reduced, plating copper onto theelectrode. The terms "intercalation" and "insertion" electrode in thiscontext is generally used to refer to arrangement providing forexpulsion or incorporation of ionic species from or into the electrodeupon oxidation or reduction of that electrode. An example of such anelectrode is the sodium tungstate electrode described in the Phippspatents U.S. Pat. Nos. 4,747,819 and 4,744,787, supra. Other examples ofsuch electrodes are the iridium oxide electrodes of U.S. Pat. Nos.4,679,572 and 4,717,581; and, Robblee, L. S. et al., J. Electrochem.Soc., Vol. 130, No. 3 p. 731-733 (1983); Pickup, P. G. et. al., J.Electroanal. Chem., Vol. 220 p. 83-108 (1987); and, Dautremont-Smith, W.C.; Displays, p. 67-80 (April 1982); all of which incorporated herein byreference. The particular, specific, nature of the primary electrodewill be dependent upon the particular transport to be conducted.

The primary electrode arrangement may comprise a single electrode orplurality of electrodes. It may comprise a porous grid or have adifferent structure. In general what is required, as indicated above, isan effective dispersive electrical contact with the gel matrix.

3. The Secondary Electrode

The secondary electrode may be constructed in any of a variety ofmanners, and may include any of the types of electrodes described abovefor the primary electrode arrangement. The secondary electrode should beselected to obtain selected changes in ionic species concentrations inthe active electrode reservoir. Such changes or modifications would notbe accomplished if the secondary electrode arrangement were constructedand operated identically to the primary electrode arrangement. Theparticular, specific, nature of the secondary electrode arrangement tobe used in any given system will be dependent upon the effect on ionpresence in the reservoir to be achieved, in accordance with theprinciples described herein.

4. The Remote Electrode Arrangement

The remote or companion electrode arrangement may be constructed of anyof a variety of appropriate means utilized in electrotransport systems.The electrode arrangement may comprise, for example, electrodes asdescribed above for the primary electrode arrangement and/or thesecondary electrode arrangement. It will in general, of course, beoperated in a manner opposite to that of the net manner of the primaryand secondary electrode arrangements. That is, the companion electrodeis selected to obtain the desired current flow through the subject,during electrotransport.

It will be understood that there is no basic principle requiring thatthe remote electrode not be involved in a drug delivery. That is, drugor therapeutic ion delivery from the remote electrode reservoir may beconducted simultaneously with the drug and/or selective ion deliveryfrom the primary electrode reservoir arrangement, if desired. Thus, thepresent invention includes within its scope an arrangement whichinvolves drug delivery from both reservoirs and appropriate secondaryelectrode arrangements within each of the reservoirs for control ofionic species concentrations therein.

5. Some Examples of Constructions and Methods According to the PresentInvention

The general principles of the present invention will be furtherunderstood from the following examples. The examples are intended toindicate how the basic principles may be applied, and variousconstructions that may be used for their application. It will beapparent from the examples that a wide variety of systems could bedeveloped for specific control of therapeutic ion delivery.

a. Use of the Secondary Electrode to Control PH in the Active ElectrodeReservoir

An example of the use of the present invention to control pH (i.e.,hydronium ion content) is as follows. Iridium oxide is an electrochromicmaterial which can be reversibly oxidized and reduced. Oxidation ofIr(III) to Ir(IV) causes a hydronium ion to be released according to thereaction:

    Ir(OH).sub.n,→IrO.sub.x (OH).sub.n-x +xH.sup.+ +xe.sup.-

This oxidation reaction occurs at about 0.7 volts (versus Ag/AgCl).

FIG. 5 shows experimental results for the use of an iridium oxide coatedwire to change the pH of 1 ml of a 0.05 molar (M) NaCl aqueous solution.As illustrated in the figure, the hydronium ion content of the solutionwas altered by two orders of magnitude by application of current of 10to 25 microamps for several minutes. The figure also indicates that thepH can be decreased by application of an oxidative potential andincreased by use of a reductive potential.

In pharmaceutical preparations, the hydronium ion content can often becritical in determining the stability, charge and biocompatibility ofthe preparation. A common method previously used for fixing the pH at adesired level has been through the use of buffering agents (for example,citrate and/or phosphate salts). The use of such buffering agents inpharmaceutical preparations for iontophoretic drug delivery systems cancause reduced efficiency of drug delivery, due to the introduction ofnon-drug ions (i.e., extraneous ions). For example, the use of a sodiumphosphate buffer in the active electrode reservoir for the iontophoreticdelivery of hydromorphone (delivered from an anode reservoir as acation) would result in delivery of both hydromorphone cation and sodiumion. A sodium ion is much more mobile than a hydronium ion, so twoproblems would result: inefficient utilization of the power source(battery) of the device, since much of the current will be handled bytransport of sodium ions instead of hydromorphone ions; and, inabilityto maintain a constant delivery rate of hydromorphone ion, for thereasons stated hereinabove. Similar inefficiencies would result fromcodelivery of phosphate (or citrate) anion with a drug ion delivered asan anion (for example, salicylate) during iontophoresis.

According to the present invention, then, a secondary electrode operableto oxidize Ir(III) to Ir(IV) [or reversibly operable to reduce Ir(IV) toIr(III)] can be used to selectively adjust pH in the system as desired.Thus, pH can be made stable without additional buffering agents. Thatis, a drift in pH during operation of the primary electrode could becompensated by oxidation or reduction of the iridium oxide of thesecondary electrode.

Continual and constant adjustment, via feedback, could be accomplishedby providing a pH sensor in the system in communication with controlmeans for the iridium oxide electrode. It will be understood that thisapplication of the methods of the present invention is to maintainconstant pH, and not to maintain a constant molar ratio for the targetspecies. In fact, in this application the molar ratio for the targetspecies will tend to decrease in time, if the only extraneous ions arethe hydronium/hydroxyl ions.

Constant current for the system could be maintained through appropriateelectronic circuitry means to maintain a balance of current among all ofthe electrodes in the system. Thus, for example, if the iridium oxideelectrode was being used as an anode in the system wherein the primaryelectrode arrangement was also used as an anode, as the current to thesecondary electrode arrangement is increased the current to the primaryelectrode arrangement could be simultaneously decreased to maintain aconstant total of current in the system.

As with an iontophoretic device which delivers a therapeutic ion,control of reservoir pH is important for an electro-osmotic(electrotransport) device where an uncharged (neutral) therapeutic agentis delivered into the target tissue due to an applied electromotiveforce. For example, consider an anode reservoir contain a neutralpolypeptide therapeutic agent suspended or dissolved therein and alsocontaining cations such as Na⁺ (added as the salt, e.g. NaCl). When theprimary electrode, for example silver, is operated as an anode (to formAgCl), migration of Na⁺ due to the applied electromotive force willresult in loss of solvent (water) from the reservoir and the polypeptidedissolved therein. Loss of solvent from the reservoir can also result inloss of other agents present in the reservoir such as buffering agents.Polypeptide stability, in general, is dependent on the pH of thereservoir; and, therefore, loss of buffering capacity could result in adetrimental change in reservoir pH with time leading to polypeptidedegradation. To counteract loss of buffering agent from the reservoir,the secondary electrode (e.g. iridium oxide) would be operated so as tocreate or remove H⁺ /OH⁻ ion and maintain a preferred reservoir pH in amanner analogous to the iontophoretic device discussed above.

This principle can, of course, be extended to include the replacement orremoval of any ion in the active reservoir of an electro-osmotic deviceby operation of a suitable secondary electrode. For example, in thepreceding discussion of electro-osmotic polypeptide delivery, loss ofNa⁺ can be maintained at a preferred concentration within the reservoirby oxidation of a secondary electrode composed of sodium tungstate asdiscussed in Section 5d to follow.

b. Use of the Secondary Electrode to Convert Drug Base or Drug Acid toDrug Ion in the Electrode Reservoir

Many drug moieties are available in "free base" or "free acid" form.Such drugs are sparingly soluble in water, and are sometimes more stablethan the salt form (ionic form) of the drug. The principles described inthis section provide practical means for iontophoretic delivery of thedrug "free base" or "free acid". Use of a hydronium iongenerating/absorbing secondary electrode (for example an iridium oxideelectrode) can be used to create in situ the charged form of the drug,which can then be iontophoretically delivered.

For example, if the anode reservoir contains the drug-base hydromorphone(alkaloid) suspended in a hydrogel at pH 8, than approximately one-halfof the alkaloid will be uncharged. Oxidation of a secondary electrodecomposed of a iridium oxide (coated on a conductive substrate material)would generate hydronium ion via the reaction presented in the immediateproceeding section.

The current and duration of the operation of the iridium oxide secondaryelectrode would depend on the amount of hydromorphone alkaloid presentin the reservoir. Preferably, only a stoichiometric amount of H⁺ wouldbe generated by the secondary electrode, so as to convert essentiallyall of the alkaloid to ionic hydromorphone, thus avoiding the generationof excess H⁺. The current/time profile for operation of the secondaryelectrode could be preprogrammed or could be controlled by a pH sensorpresent in the reservoir. The particular rate of generation of H⁺ by thesecondary electrode would preferably be no greater than the rate ofconversion of alkaloid to hydromorphone cation. This would insure that ahydronium ion does not substantially compete with hydromorphone cationfor transport, as would be the case of H were generated at too large ofa rate, even though only generated in a stoichiometric amount in total.

The primary electrode for this example could be any of the previouslydiscussed arrangements, but would preferably be selected so as togenerate little or no H⁺ or OH⁻ ion. In other words, conversion of thealkaloid to the cation would primarily be controlled by operation to thesecondary electrode.

If only a primary electrode system capable of generating H⁺ ion wereused, its operation would result in either too great a rate of H⁺generation, or too great a total of H⁺ generation (i.e. greater thanstoichiometric) in order to achieve a desired rate of transport. Thiswould lead to pH instability and loss of efficient delivery of ahydromorphone ion.

Use of an excessive amount of hydromorphone alkaloid in the reservoirmay in some instances prevent a pH instability, but it would result inwaste of hydromorphone and create a concern for safe disposal of theiontophoretic system after use.

Alternatively, the hydromorphone alkaloid could be converted to thecationic form by removal of OH⁻ in the reservoir, upon operation of thesecondary electrode. Removal of OH⁻ in a water-containing reservoirresults in a lowering of the pH of the reservoir, and thus a conversionof the alkaloid to the cationic form.

In the case where the drug to be delivered is available or can beproduced in the acid form (uncharged) then the secondary electrodesystem would be used to generate hydroxyl ion or remove hydronium ion.For example, salicylic acid is a sparingly soluble drug. Delivery ofsalicylate could be a accomplished by the placement of the acid form inthe cathode reservoir of an iontophoretic device, with a follow-up stepof conversion to salicylate anion by generation of OH⁻ via reduction ofwater at a glassy carbon secondary electrode, or by removal of H⁺ fromthe cathode reservoir by reduction of an iridium oxide secondaryelectrode.

For such a system, the primary electrode, which could be a plating orsacrificial electrode, but preferably not substantially H⁺ or OH⁻generating/removing, would supply additional electromotive force suchthat the total force (primary+secondary) would drive the salicylateanion into the skin at an appropriate rate.

The limitations on the rate and duration of OH⁻ /H⁺ generation/removal(i.e. current) by the secondary electrode would be similar to thosediscussed above in the hydromorphone alkaloid example.

The use of the secondary electrode, as opposed to the primary electrode,to generate or remove hydronium or hydroxyl ion is advantageous in thata stoichiometric amount of H⁺ or OH⁻ ion needed to convert free base orfree acid drug to the ionic form can be efficiently generated. That is,the primary electrode arrangement can be selected to generateappropriate electromotive force for ion transport without simultaneousgeneration of hydronium or hydroxyl ion. This would generally avoid theproduction of excess H⁺ or OH⁻ in the system, facilitating patientcomfort and good control over pH and ion delivery.

c. Use of the Secondary Electrode to Create a Mixture of Charged andUncharged Drug for Control of Total Drug Delivery (passive and active)

In general, uncharged organic species penetrate the skin more readilythan charged organic species when little or no electromotive force isapplied to the reservoir. This is known as "passive" or "diffusive" drugdelivery. This observation leads to a preferred drug delivery systemwhere the ratio of charged to uncharged drug (e.g. hydromorphone orsalicylate) can be altered so that delivery is: mostly or wholly due todiffusion of uncharged drug; or, mostly or wholly due toelectrotransport of charged (ionic) drug; or, to a combination ofdiffusion and electrotransport. A preferred combination of delivery bydiffusion and electrotransport via creation of a preferred charged touncharged drug ratio in the reservoir can be accomplished throughmaintenance of a particular pH upon use of a secondary electrode systemas described above. This can lead to a optimized energy efficientdelivery system.

For example, if hydromorphone is required by a patient at a low doserate for most of the day to control pain, but at a much higher dose rateduring part of the day, then the preferred delivery system discussedabove could be operated in a mostly diffusive mode (i.e. at a reservoirpH where most of the drug is uncharged) when the low dose rate isrequired and in an electromotive mode (i.e. at a pH where some or all ofthe drug is cationic and the primary electrode supplies electromotiveforce) when the higher dose rate is required.

In general terms, this preferred drug delivery system can alter the typeand size of the force applied to the drug species by adjusting the pH ofthe reservoir and the electric potential (voltage) supplied by theprimary electrode. The type of force can be shifted from mostly chemicalin nature (i.e. resulting from a chemical potential gradient) to mostlyelectromotive in nature (i.e. resulting from an electrical potentialgradient). Optimal energy efficiency is achieved by matching thetherapeutic dose needed by the patient to the least energy consumingcombination of diffusive and electromotive force needed to meet the doserequirement. Generally, the least energy consuming combination would bethat which is as diffusive in nature as possible.

In a special instance wherein the uncharged drug diffuses through thetissue (skin) at a rate sufficient to meet the highest dose requirementof the patient, but where a lower dose rate is required by the patientperiodically through the day, then the pH at the reservoir could bealtered by the secondary electrode to increase the fraction of chargeddrug in the reservoir and thus lower drug delivery.

In this latter instance, primary and secondary electrode systems areneeded in the active electrode reservoir but no remote or groundelectrode is required, since only a diffusive process is required todeliver a sufficient (therapeutic) quantity of the drug. Thus, thelatter example is not an electrotransport, but rather is an applicationof principles described herein to facilitate a diffusive process, byproviding an electrode system within the reservoir for drug delivery.The electrode system would generally include first and second operableelectrode arrangements, selected for control of pH. A sensor system,pre-programed system or both could be used for control.

This principle of use of two electrodes in the active or deliveryreservoir to alter reservoir conditions and thus change permeability oftherapeutic agent can be extended to include chemical or electrochemicalalteration. For example, conversion of a drug precursor in the reservoirto an active and/or more permeable form. This conversion can beconducted before placement of the reservoir against the skin, or after.It may be conducted continuously or selectively. It will be understoodthat the technique may be applied if the drug has a polar and unpolar(or less polar) form, of different mobility, even if neither form ischarged, provided the electrodes can be used to convert the drug betweenthe two forms. Of course, if the drug has both charged and unchargedforms, the charged form will be the more polar.

d. Use of the Secondary Electrode to Control the Inorganic Ion Contentof the Active Electrode Reservoir

Inorganic ions such as Na⁺, K⁺, Ca²⁺, Cl⁻, SO₄ ²⁻, HCO₃ ⁻, and PO₄ ³⁻may be present in the active electrode reservoir, for example asadditives to enhance some property of the reservoir (e.g., drugstability, pH stability, conductivity and/or biocompatability) or theirpresence may be inadvertent or unavoidable (e.g., impurities present inreservoir ingredients, pre-existing ions on the skin surface, taken-upduring iontophoresis especially in a reverse polarity device asdescribed by Lattin, G. A., U.S. Pat. No. 4,406,658). Changes in theconcentration of inorganic ions in the active reservoir duringelectrotransport can result in changes in the delivery rate of thetarget ion as discussed previously, and as reported in Experiment 1which follows. A secondary electrode which releases/generates orabsorbs/removes inorganic ions upon oxidation or reduction can be usedto control the inorganic content of the active reservoir in a manneranalogous to the use of an iridium oxide electrode to control the pH,discussed previously. One class of electrodes which releases or removesNa⁺, K⁺, and Ca²⁺ and other inorganic ions are inorganic intercalationor insertion materials. A specific example is sodium tungsten-bronzewhich releases Na⁺ when oxidized and absorbs Na⁺ when reduced, via thereversible reaction:

    Na.sub.x WO.sub.3 ⃡Na.sub.x-1 WO.sub.3 +Na.sup.+ +e.sup.-

Other possible secondary electrode materials are graphite intercalationcompounds, specifically:

    nC+Na.sup.+ +e.sup.- ⃡C.sub.n Na

for release or removal of Na⁺ ; or,

    C.sub.n FeCl.sub.2 +Cl.sup.- ⃡C.sub.n FeCl.sub.3 +e.sup.-

for release or removal of Cl⁻.

Another class of possible electrode materials are conductive polymers,for example, those described by Miller, L. L. et al in J. Am. Chem.Soc., Vol. 106, pages 6861-6863; J. Electroanal. Chem., Vol. 261, pages147-164; J. Electroanal. Chem., Vol. 247, pages 173-184. The polymerelectrodes can be polypyrrols, polyanilines, polythiophenes, andmodifications thereof. In general, use of polymeric electrodes resultsin the release or absorption of anions and cations (organic orinorganic) to maintain charge neutrality locally within theirstructures. For example, a composite electrode composed ofpoly(N-methylpyrrolylium) and poly(styrenesulfonate) will cathodicallyabsorb cations and anodically release cations. Anions can be anodicallyabsorbed or cathodically released by oligomeric 3-methoxythiophene.

For example, consider as an anode reservoir of the electrode transportdevice a reservoir which contains the drug cation hydromorphone (as theHCl salt). Also, assume that the inorganic extraneous ion Na⁺ is alsopresent in the anode reservoir. During operation of this device, sodiumion will be depleted from the reservoir at a greater rate than is thehydromorphone, due to the relatively high mobility of Na⁺ through skinas compared with hyaromorphone. As shown in FIG. 1 and discussed inExperiment 1 below, the result will be an increase in the hydromorphonedelivery rate with time, at constant current. To maintain a constanthydromorphone delivery rate with time, a secondary electrode whichgenerates Na⁺ at a rate necessary to maintain a constant molar fractionof the hydromorphone in the reservoir can be used.

e. Use of the Secondary and Primary Electrodes in the Active Reservoirto Convert Drug Therein to an Inactive Form

In general, after termination of drug delivery from an electrotransportdevice, some drug will remain in the active reservoir. It may bedesirable to "inactivate" or "degrade" or "convert" the drug to aninactive or nonextractable form to prevent inadvertent or intentionalpost-treatment use of the drug. This conversion of drug to an inactiveform after device removal from the patient can be accomplished by use ofthe primary and secondary electrode by allowing one to act as the"counter" electrode for the other.

Either electrode (or both) can cause direct electrochemical degradationof the drug if the electrode potential is sufficiently large so thatoxidation or reduction of the drug will occur (oxidation at the anode,reduction at the cathode). For example, electrochemical degradation ofhydromorphone will occur at a platinum or glassy carbon electrode if theanodic potential exceeds 500 mV (versus Ag/AgCl).

The primary or secondary electrode material can be selected and operatedso as to cause creation of a species which results directly orindirectly in the conversion of drug in the active reservoir to aninactive or nonextractable form. For example, the secondary electrodecould be iridium oxide or platinum or another material which cangenerate hydronium or hydroxyl ion. Many drugs will rapidly degrade athigh and/or low values of pH and therefore use of a secondary electrodeto change the pH (as described previously) can result in conversion ofthe drug to an inactive form.

Alternatively, the. primary or secondary electrode material can beselected so that its operation after device removal from the patientcauses the release or generation of a chemical species which then reactswith, complexes with, or otherwise inactivates the drug, or converts thedrug to a nonextractable form. For example, if the anode reservoircontains hydromorphone and the secondary electrode is silver, thenoperation of the secondary electrode as an anode after device removalwill generate silver ion which will cause degradation of hydromorphoneand additionally create a silver-rich active reservoir from whichrecovery of hydromorphone would require extensive processing. In thisexample, the silver secondary electrode may be dormant duringelectrotransport of drug from the device when on the patient and beactivated when the device is removed from the body of the patient. Whenthe device is removed, the control circuit would cause the primaryelectrode to serve as a cathode and the silver secondary electrode as ananode and as a result ionic current would flow between the secondary andprimary electrodes (the remote electrode is not functional in this modeof operation). The primary electrode could also cause inactivation ofthe drug by a separate mechanism, for example, production of hydroxylion or electrochemical reduction of the drug (when operated as acathode).

In general, the inactivation of drug in the active reservoir can beaccomplished upon device removal if the active reservoir contains atleast two electrodes so that an electrical potential can be appliedbetween them such that one or both of the electrodes can inactivate thedrug by the mechanisms discussed above (pH control, electrochemicaldegradation, chemical reaction, and/or reservoir contamination, e.g.,with silver ion).

f. Experimental Examples

Experiment 1

The following experiment illustrates that, in the presence of highlymobile extraneous ions, direct delivery rate is shown to increase intime at constant current.

Aqueous solutions of hydromorphone (HM) and selected inorganic ions wereprepared at total cation concentrations of 0.1 molar. The inorganic ionsemployed were sodium, potassium, calcium and magnesium, used as thechloride salts. The solutions were placed in the donor compartment of atwo-chamber, flow-through glass cell modified to accommodate a silveranode and a silver chloride cathode. Dermatomed pig skin was placedbetween the donor and receptor compartments. The contact area betweenthe donor solution and the skin was 8 cm². A 0.1 molar sodium chlorideaqueous solution was pumped through the receptor compartment at 3 ml perhour. The experiment was performed in triplicate at a current of 1milliamp (i.e., 125 microamps per cm²).

In Table 1 below, the results from four solutions are reported. The foursolutions comprised one each of the four cations in solution withhydromorphone as hydromorphone hydrochloride. In Table 1, both the molarconcentration and mole fraction, initial and final, are reported. Bycomparison of these figures, one observes that the concentrations ofboth the hydromorphone and the extraneous ion decreased during operationof the cell. Also, it is observed that the molar fraction of the moremobile extraneous ion was decreasing, while the molar fraction of theless mobile hydromorphone ion was increasing.

In FIG. 1, a plot of the rate of delivery of the hydromorphone (inmicrograms per hour) at various time periods is illustrated. The graphshows a linear increase in the hydromorphone delivery rate observed as afunction of time, for solutions initially containing approximately equalmolar concentrations of HM⁺ and inorganic ions.

                  TABLE 1                                                         ______________________________________                                                   Molar                                                                         Concentration   Mole Fraction                                      Solution                                                                              Ion      Initial                                                                              Final    Initial                                                                            Final                                   ______________________________________                                        1       Na       0.047  0.029    0.435                                                                              0.357                                           HM       0.061  0.053    0.565                                                                              0.643                                   2       K        0.049  0.021    0.497                                                                              0.312                                           HM       0.049  0.046    0.503                                                                              0.688                                   3       Mg       0.048  0.038    0.481                                                                              0.445                                           HM       0.051  0.048    0.519                                                                              0.555                                   4       Ca       0.049  0.039    0.490                                                                              0.437                                           HM       0.051  0.050    0.510                                                                              0.563                                   ______________________________________                                    

Experiment 2

That the relationship between applied current and delivery of a targetion, for a system involving no extraneous ions, is linear is illustratedby the following example. The example is also reported in the literatureat Phipps et al. "Transport of Ionic Species Through Skin," supra(1988). A two-compartment, vertical glass diffusion cell was used. Asilver/silver chloride cathode was introduced into the receptorcompartment by inserting the electrode wire into an inlet port. Excisedrabbit, pig or human skin, approximately 8 cm² in area, was placed on amesh which served as a support to the excised skin. The donorcompartment, the excised skin and the receptor compartment were clampedtogether. One molar aqueous solution of the drug chloride was preparedand poured into the donor compartment. The cations used in the studywere lithium, sodium, magnesium, potassium, calcium, salicylate,pyridostigmine and propranolol.

A silver anode was placed in the donor compartment which contained 7 mlof drug solution. A septum cap was placed on the donor compartment tominimize loss due to evaporation. The cathode and anode wires for eachcell were connected to a nine-channel power source. Experiments witheach type of skin were run in duplicated currents between 0 and 2milliamps for 24 hours.

A flow-through diffusion cell system, which allowed for nine differentexperiments to be run simultaneously, was employed. An aqueous solutionof 0.1 M NaCl was supplied to a nine-channel peristaltic pump and pumpedto the flow rate of 6 ml per hour into the receptor compartments of thenine diffusing cells. The water jacketed receptor compartment wasmaintained at 37° C. by a circulator bath, and the receptor fluid wasstirred by placing the cells in the nine-cell magnetic drive console.Samples were continuously collected through the sampling outlet of thereceptor compartment at two-hour intervals by nine-channel fractioncollectors. The iontophoretic current for each cell was controlled by aconstant current power source.

The drug content of the receptor compartment was determined by atomicabsorption spectrophotometry (for inorganic ions) or by high-performanceliquid chromatography (for organic ions).

A linear dependance of the rate of drug delivery and current wasobserved for each of the ions studied. An example of this is indicatedin FIG. 6, which shows a plot of lithium delivery rate as a function ofthe current for pig and rabbit skin. In general, the efficiency of drugdelivery was found to decrease with increasing molecular weight and withincreasing ionic charge.

Experiment 3

The independence of drug delivery rate on concentration of the drugspecies, above a threshold concentration and at constant current, isdemonstrated by the following example. The example was also reported inPadmanabhan et al., "In Vitro and In Vivo Evaluation of TransdermalIontophoretic Delivery of Hydromorphone," supra (1990). For the in vitrostudy, a two-compartment vertical glass diffusion cell was used. Asilver chloride cathode was placed in the receptor compartment (4 mlcapacity) and a silver mesh anode in the donor compartment. Excised pigskin was placed on a Delrin® support fixture and clamped in placebetween the two compartments with the stratum corneum facing the donorcompartment. The contact area between the donor solution and the excisedskin was 8 cm². Pig skin was obtained from the mid-dorsal region ofdomestic, weanling pigs by dermatome at a thickness of about 600microns. Skin samples were stored frozen prior to use.

The jacketed receptor compartment was maintained at a temperature ofabout 37° C. by a circulating water bath, and a 0.1 M NaCl solution waspumped through the receptor chamber at a flow rate of about 3 and 6 mlper hour. The donor compartment was filled with 7 ml of hydromorphonehydrochloride (HMHCl) solution at selected concentrations from 0.01molar (10 millimolar) to 0.8 molar (800 millimolar). The anode andcathode were connected to a constant current power supply accurate towithin 5% of a set point value. Experiments were performed at currentsof up to 2.0 milliamperes (mA) for 24 hours.

In a typical experiment, the HMHCl solution was placed in the donorcompartment for 18 hours prior to the application of current. This wasdone to ensure that no leaks were present in the donor compartment priorto iontophoresis, and to allow for determination of the passivehydromorphone flux through each skin sample. After 18 hours, the donorcompartment was emptied, rinsed and filled with fresh drug solution. Aconstant current was then applied for 24 hours, followed by 24 hours ofpassive delivery. In some experiments, the pre-iontophoretic passivephase and/or the post-iontophoretic passive phase were not performed.

During the 66-hour duration of the typical experiment, samples werecollected continuously at two-hour intervals. The weight of eachreceptor sample was recorded, and the hydromorphone concentration ofselected samples was determined by HPLC using UV detection at 280nanometers. A 5 nanometer C18 column (Dupont Instruments, Wilmington,Del.) was used. The mobile phase was comprised of 59% 0.005 M heptanesulfonic acid, 40% methanol and 1% acetic acid. The flow rate was set at1 ml per minute.

Steady-state delivery rates were determined for each skin sample bymultiplying the steady-state receptor concentration (achieved inapproximately 10 hours) by the receptor flow rate, which was calculatedfrom the weight of each two-hour receptor sample. Average steady-staterates for each skin sample were calculated for five consecutive valuesobserved between 12 and 24 hours after application of the current.

In Table 2 below, a comparison of average steady-state delivery ratesfor pig skin from aqueous hydromorphone HCl solutions at differentconcentrations (where n= the number of skin samples) is presented. Ascan be seen, the average rate of delivery (microgram per hour) wasrelatively constant, regardless of the drug concentration.

                  TABLE 2                                                         ______________________________________                                        A comparison of the average steady-state delivery rates                       through pig skin from aqueous hydromorphone HCl solutions                     at different concentrations.                                                  Drug                  Average                                                 Concentration         Steady-State Rate                                       (millimolar)    n     (μg/hr) ± SD                                      ______________________________________                                        10              3     1049 ± 183                                           30              3     1269 ± 43                                            100             19    1150 ± 159                                           400             3     1118 ± 180                                           800             3     1000 ± 71                                            ______________________________________                                    

It will be understood that experiments 1, 2 and 3 reported abovegenerally provide the background observations described in SectionsA1-A3 of the detailed description above, and which provide some of thebasis for applications of the present invention to control extraneousion concentrations in active electrode reservoirs.

What is claimed is:
 1. A method of operating an electrode system, themethod including steps of:(a) providing a primary electrode systemincluding:(i) a first reservoir including at least --one--firstreservoir electrode and an electrolyte; and (ii) a second reservoirincluding at least --one--second reservoir electrode and an electrolyte;the second reservoir being spaced from the first reservoir; (b)providing a secondary electrode system including:(i) a secondaryelectrode, located within the first reservoir and isolated from directelectrical contact with the first reservoir electrode; and (ii) acompanion electrode; (c) selectively operating the primary electrodesystem to provide electromotive movement of a species between areservoir and a subject; and (d) selectively operating the secondaryelectrode system to generate a potential between the secondary electrodeand the companion electrode, wherein the companion electrode is the atleast one second reservoir electrode, such that an effect ofelectrochemical reactions involving the secondary electrode system oncontents of the reservoir is different from that of the primaryelectrode system.
 2. A method according to claim 1 wherein:(a) the stepof selectively operating the secondary electrode system comprisesgenerating a potential between the secondary electrode and the companionelectrode in a manner lowering a presence of a material in a reservoir.3. A method according to claim 1 wherein:(a) the step of directingelectrical current between a first reservoir electrode and the secondreservoir electrode is conducted as a step of a diagnostic procedure. 4.A method of operating an electrode system; the method including thesteps of:(A) placing an electrode system in electrically conductivecontact with a skin surface of patient; the electrode systemincluding:(a) a primary electrode system including:(i) a first reservoirincluding at least --one--first reservoir electrode and an electrolyte;and (ii) a second reservoir including at least --one--second reservoirelectrode and an electrolyte; the second reservoir being spaced from thefirst reservoir; and (b) a secondary electrode system including:(i) asecondary electrode, located within the first reservoir and isolatedfrom direct electrical contact with the at least one first reservoirelectrode; and (ii) a companion electrode; (B) directing an electricalcurrent between the at least one first reservoir electrode and the atleast one second reservoir electrode, through the patient; and (C)operating the secondary electrode system by generating a potentialbetween the secondary electrode and the companion electrode, wherein thecompanion electrode is a second reservoir electrode, to lower a presenceof a selected material within a reservoir.
 5. A method according toclaim 4 wherein:(a) the step of operating the secondary electrode systemis conducted after the step of directing an electrical current between afirst reservoir electrode and a second reservoir electrode has beensuspended.
 6. A method according to claim 4 wherein:(a) the secondaryelectrode system is operated with the secondary electrode as an anodeand a second reservoir electrode as a cathode.
 7. A method according toclaim 4 wherein:(a) the step of operating the secondary electrode systemcomprises a step of applying a sufficient potential to oxidize theselected material at the secondary electrode.
 8. A method according toclaim 4 wherein:(a) the secondary electrode is a platinum electrode. 9.A method according to claim 4 wherein:(a) the step of operating thesecondary electrode system comprises a step of generating hydronium ionswithin the first reservoir.
 10. A method according to claim 4wherein:(a) during at least a portion of the step of directing anelectrical current between the at least one first reservoir electrodeand the at least one second reservoir electrode, the at least one firstreservoir electrode is operated as a cathode.
 11. A method according toclaim 4 wherein:(a) the step of operating the secondary electrode systemis conducted to lower a presence of an active drug by converting it toan inactive form.
 12. A method according to claim 4 wherein:(a) the stepof directing an electrical current between the first at least onereservoir electrode and the at least one second reservoir electrodeincludes conducting electro-osmosis.
 13. A method according to claim 12wherein:(a) the electro-osmosis includes transferring an unchargedmaterial from the first reservoir to the patient.
 14. A method accordingto claim 4 wherein:(a) the step of directing electrical current betweenthe at least one first electrode and the at least one second reservoirelectrode is conducted as a step of a diagnostic procedure.
 15. A methodof conducting operation of an electrode system; the method including thesteps of:(A) placing an electrode system in electrically conductivecontact with a skin surface of patient; the electrode systemincluding:(a) a primary electrode system including:(i) a first reservoirincluding at least --one--first reservoir electrode and an electrolyte;and (ii) a second reservoir including at least --one--second reservoirelectrode and an electrolyte; the second reservoir being spaced from thefirst reservoir; and (b) a secondary electrode system including:(i) asecondary electrode, located within the first reservoir and isolatedfrom direct electrical contact with the at least one first reservoirelectrode; and (ii) a companion electrode; (B) directing an electricalcurrent between the at least one first reservoir electrode and the atleast one second reservoir electrode, through the patient; and (C)operating the secondary electrode system to generate a potential betweenthe secondary electrode and the companion electrode to lower a presenceof a selected material within the at least one first reservoir, whereinthe companion electrode is the at least one first reservoir electrodeand the step of operating the secondary electrode system is conductedafter the step of directing an electrical current between the at leastone first reservoir electrode and the at least one second reservoir hasbeen completed.
 16. A method according to claim 15 wherein:(a) thesecondary electrode is operated as an anode and the at least one firstreservoir electrode is operated as a cathode.
 17. A method according toclaim 15 wherein:(a) the secondary electrode is operated as an inertelectrode and the first electrode is operated as a sacrificialelectrode.
 18. A method according to claim 15 wherein:(a) the at leastone first reservoir electrode is an Ag/AgCl electrode.
 19. A methodaccording to claim 15 wherein:(a) the step of operating the secondaryelectrode system is conducted after the electrode system is separatedfrom contact with the patient.
 20. A method according to claim 15wherein:(a) the step of directing electrical current between the atleast one first reservoir electrode and at least one the secondreservoir electrode is conducted as a step of a diagnostic procedure.